Sex-specific cytokine responses and neurocognitive outcome after blood transfusions in preterm infants.

BACKGROUND: The objective of this study was to determine sex-specific differences in inflammatory cytokine responses to red blood cell (RBC) transfusion in preterm infants in the neonatal period and their relationship to later neurocognitive status. METHODS: Infants with a birth weight <1000 g and gestational age 22-29 weeks were enrolled in the Transfusion of Prematures (TOP) trial. The total number of transfusions was used as a marker of transfusion status. Nineteen cytokines and biomarkers were analyzed from 71 infants longitudinally during the neonatal period. Twenty-six infants completed the Bayley Scales of Infant & Toddler Development, 3rd Edition (Bayley-III) at 12 months' corrected age. RESULTS: Nine cytokine levels were significantly elevated in proportion to the number of transfusions received. Of those, one cytokine showed a sex-specific finding (p = 0.004): monocyte chemoattractant protein-1, MCP-1, rose substantially in females (8.9% change per additional transfusion), but not in males (-0.8% change). Higher concentrations of MCP-1 exclusively were associated with worse Bayley-III scores: decreased cognitive raw scores (p = 0.0005) and motor scaled scores (p < 0.0001). CONCLUSIONS: This study provides evidence of a sex-specific difference in the inflammatory response to RBC transfusions during neonatal life, with MCP-1 levels rising only in females and inversely correlating with neurocognitive status at 12 months old. IMPACT: It is important to understand the risk factors for abnormal neurodevelopment in preterm infants, including anemia and RBC transfusion, in order to improve outcomes and provide potential targets for therapy. Our study investigates and provides the first evidence of sex-specific differences in inflammatory cytokine responses to RBC transfusions in preterm infants in the neonatal period, and their relationship to later cognitive outcomes. This study critically suggests that different transfusion thresholds may have a sex-specific effect on neurodevelopment: females have worse cognitive outcomes with increased number of transfusions, while males have worse outcomes with lower number of transfusions.

Sex-specific alterations in preterm brain.

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

Correction: Sex-specific alterations in preterm brain.

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

Frontal, Striatal, and Medial Temporal Sensitivity to Value Distinguishes Risk-Taking from Risk-Aversive Older Adults during Decision Making.

Aging compromises the frontal, striatal, and medial temporal areas of the reward system, impeding accurate value representation and feedback processing critical for decision making. However, substantial variability characterizes age-related effects on the brain so that some older individuals evince clear neurocognitive declines whereas others are spared. Moreover, the functional correlates of normative individual differences in older-adult value-based decision making remain unclear. We performed a functional magnetic resonance imaging study in 173 human older adults during a lottery choice task in which costly to more desirable stakes were depicted using low to high expected values (EVs) of points. Across trials that varied in EVs, participants decided to accept or decline the offered stakes to maximize total accumulated points. We found that greater age was associated with less optimal decisions, accepting stakes when losses were likely and declining stakes when gains were likely, and was associated with increased frontal activity for costlier stakes. Critically, risk preferences varied substantially across older adults and neural sensitivity to EVs in the frontal, striatal, and medial temporal areas dissociated risk-aversive from risk-taking individuals. Specifically, risk-averters increased neural responses to increasing EVs as stakes became more desirable, whereas risk-takers increased neural responses with decreasing EV as stakes became more costly. Risk preference also modulated striatal responses during feedback with risk-takers showing more positive responses to gains compared with risk-averters. Our findings highlight the frontal, striatal, and medial temporal areas as key neural loci in which individual differences differentially affect value-based decision-making ability in older adults. SIGNIFICANCE STATEMENT: Frontal, striatal, and medial temporal functions implicated in value-based decision processing of rewards and costs undergo substantial age-related changes. However, age effects on brain function and cognition differ across individuals. How this normative variation relates to older-adult value-based decision making is unclear. We found that although the ability make optimal decisions declines with age, there is still much individual variability in how this deterioration occurs. Critically, whereas risk-averters showed increased neural activity to increasingly valuable stakes in frontal, striatal, and medial temporal areas, risk-takers instead increased activity as stakes became more costly. Such distinct functional decision-making processing in these brain regions across normative older adults may reflect individual differences in susceptibility to age-related brain changes associated with incipient cognitive impairment.

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.

Developmental Trajectory of Height, Weight, and BMI in Children and Adolescents at Risk for Huntington's Disease: Effect of mHTT on Growth.

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.

Brain structure in juvenile-onset Huntington disease.

OBJECTIVE: To 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. METHODS: Despite 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. RESULTS: Participants 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. CONCLUSIONS: The 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.

Abnormal brain development in child and adolescent carriers of mutant huntingtin.

OBJECTIVE: The huntingtin gene is critical for the formation and differentiation of the CNS, which raises questions about the neurodevelopmental effect of CAG expansion mutations within this gene (mHTT) that cause Huntington disease (HD). We sought to test the hypothesis that child and adolescent carriers of mHTT exhibit different brain growth compared to peers without the mutation by conducting structural MRI in youth who are at risk for HD. We also explored whether the length of CAG expansion affects brain development. METHODS: Children and adolescents (age 6-18) with a parent or grandparent diagnosed with HD underwent MRI and blinded genetic testing to confirm the presence or absence of mHTT. Seventy-five individuals were gene-expanded (GE) and 97 individuals were gene-nonexpanded (GNE). The GE group was estimated to be on average 35 years from clinical onset. Following an accelerated longitudinal design, age-related changes in brain regions were estimated. RESULTS: Age-related striatal volume changes differed significantly between the GE and GNE groups, with initial hypertrophy and more rapid volume decline in GE. This pattern was exaggerated with CAG expansion length for CAG > 50. A similar age-dependent group difference was observed for the globus pallidus, but not in other major regions. CONCLUSION: Our results suggest that pathogenesis of HD begins with abnormal brain development. An understanding of potential neurodevelopmental features associated with mHTT may be needed for optimized implementation of preventative gene silencing therapies, such that normal aspects of neurodevelopment are preserved as neurodegeneration is forestalled.

Abnormal Weight and Body Mass Index in Children with Juvenile Huntington's Disease.

BACKGROUND AND OBJECTIVES: The hallmark clinical manifestation of Huntington's disease (HD), namely lower weight and BMI has been reported in prodromal HD (PreHD) adults and also in PreHD children. Here, we aim to evaluate anthropometric measures of growth and development (height, weight, body mass index (BMI)) in a group of children, adolescents, and young adults diagnosed with Juvenile Onset Huntington's Disease (JHD). METHODS: Growth measures for 18 JHD patients, documented prior to or shortly after diagnosis, were obtained through medical records. JHD growth measures were compared to a large sample (n = 274) of healthy children, as well as the Center for Disease Control (CDC) growth norms. RESULTS: After controlling for sex and age, the JHD subjects had no significant differences in height. However, they were an average of 10% lower than controls in weight and BMI. Using CDC norms, the JHD subjects had the same pattern of normal height but decrement in weight. Length of cytosine-adenine-guanine (CAG) repeat in the huntingtin gene was significantly correlated to measures of weight with longer CAG repeats being associated with more severe weight reduction. A subset of 4 subjects had measures that pre-dated onset of any symptom and were therefore prodromal JHD (preJHD). These subjects also had a significant decrement in BMI compared to CDC norms. CONCLUSIONS: Children with JHD have normal height, but significantly reduced weight and BMI, indicative of a specific deficit in body weight. As the preJHD subjects were also low in BMI, this suggests that these changes are directly due to the effect of the mutated gene on development, rather than symptom manifestation of the disease itself. Potential mechanisms of the weight decrement include energy deficiency due to mitochondrial dysfunction during development.