Mirror neuron activation in children with developmental coordination disorder: A functional MRI study.

The aim of this study was to reveal cortical areas that may contribute to the movement difficulties seen in children with Developmental Coordination Disorder (DCD). Specifically, we hypothesized that there may be a deficit in the mirror neuron system (MNS), a neural system that responds to both performed and observed actions. Using functional MRI, 14 boys with DCD (x¯=10.02 years±1.28, range=8.33-11.17 years) and 12 typically developing controls (x¯=10.10 years±1.16, range=8.02-12 years) were scanned observing, executing and imitating a finger sequencing task using their right hand. Cortical activations of mirror neuron regions, including posterior inferior frontal gyrus, ventral premotor cortex, anterior inferior parietal lobule and superior temporal sulcus were examined. Children with DCD had decreased cortical activation mirror neuron related regions, including the precentral gyrus and inferior frontal gyrus, as well as in the posterior cingulate and precuneus complex when observing the sequencing task. Region of interest analysis revealed lower activation in the pars opercularis, a primary MNS region, during imitation in the DCD group compared to controls. These findings provide some preliminary evidence to support a possible MNS dysfunction in children with DCD

Challenges of diagnostic exome sequencing in an inbred founder population

Exome sequencing was used as a diagnostic tool in a Roma/Gypsy family with three subjects (one deceased) affected by lissencephaly with cerebellar hypoplasia (LCH), a clinically and genetically heterogeneous diagnostic category. Data analysis identified high levels of unreported inbreeding, with multiple rare/novel "deleterious" variants occurring in the homozygous state in the affected individuals. Step‐wise filtering was facilitated by the inclusion of parental samples in the analysis and the availability of ethnically matched control exome data. We identified a novel mutation, p.Asp487Tyr, in the VLDLR gene involved in the Reelin developmental pathway and associated with a rare form of LCH, the Dysequilibrium Syndrome. p.Asp487Tyr is the third reported missense mutation in this gene and the first example of a change affecting directly the functionally crucial β‐propeller domain. An unexpected additional finding was a second unique mutation (p.Asn494His) with high scores of predicted pathogenicity in KCNV2, a gene implicated in a rare eye disorder, retinal cone dystrophy type 3B. This result raised diagnostic and counseling challenges that could be resolved through mutation screening of a large panel of healthy population controls. The strategy and findings of this study may inform the search for new disease mutations in the largest European genetic isolate

Nocturnal oxyhemoglobin desaturation and arteriopathy in a pediatric sickle cell disease cohort

OBJECTIVE: The purpose of this study of sickle cell disease (SCD) was to determine whether arteriopathy, measurable as intracranial vessel signal loss on magnetic resonance angiography (MRA), was associated with low nocturnal hemoglobin oxygen saturation (SpO2) or hemolytic rate, measurable as reticulocytosis or unconjugated hyperbilirubinemia. METHODS: Ninety-five East London children with SCD without prior stroke had overnight pulse oximetry, of whom 47 (26 boys, 39 hemoglobin SS; mean age 9.1 ± 3.1 years) also had MRA, transcranial Doppler (TCD), steady-state hemoglobin, and reticulocytes within 34 months. Two radiologists blinded to the other data graded arteriopathy on MRA as 0 (none) or as increasing severity grades 1, 2, or 3. RESULTS: Grades 2 or 3 arteriopathy (n = 24; 2 with abnormal TCD) predicted stroke/TIA compared with grades 0 and 1 (log-rank χ(2) [1, n = 47] = 8.1, p = 0.004). Mean overnight SpO2 correlated negatively with reticulocyte percentage (r = -0.387; p = 0.007). Despite no significant differences across the degrees of arteriopathy in genotype, mean overnight SpO2 was higher (p < 0.01) in those with grade 0 (97.0% ± 1.6%) than those with grades 2 (93.9 ± 3.7%) or 3 (93.5% ± 3.0%) arteriopathy. Unconjugated bilirubin was not associated but reticulocyte percentage was lower (p < 0.001) in those with grade 0 than those with grades 2 and 3 arteriopathy. In multivariable logistic regression, lower mean overnight SpO2 (odds ratio 0.50, 95% confidence interval 0.26-0.96; p < 0.01) predicted arteriopathy independent of reticulocyte percentage (odds ratio 1.47, 95% confidence interval 1.15-1.87; p = 0.003). CONCLUSION: Low nocturnal SpO2 and reticulocytosis are associated with intracranial arteriopathy in children with SCD. Preventative strategies might reduce stroke risk

Reduced relative volume in motor and attention regions in developmental coordination disorder: a voxel-based morphometry study.

Background and Objectives: Developmental coordination disorder (DCD) is a prevalent childhood movement disorder, impacting the ability to perform movement skills at an age appropriate level. Although differences in grey matter (GM) volumes have been found in related developmental disorders, no such evidence has been linked with DCD to date. This cross-sectional study assessed structural brain differences in children with and without DCD. Methods: High-resolution structural images were acquired from 44 children aged 7.8–12 years, including 22 children with DCD (≤16th percentile on MABC-2; no ADHD/ASD), and 22 typically developing controls (≥20th percentile on MABC-2). Structural voxel-based morphology analysis was performed to determine group differences in focal GM volumes. Results: Children with DCD were found to have significant, large, right lateralised reductions in grey matter volume in the medial and middle frontal, and superior frontal gyri compared to controls. The addition of motor proficiency as a covariate explained the between-group GM volume differences, suggesting that GM volumes in motor regions are reflective of the level of motor proficiency. A positive correlation between motor proficiency and relative GM volume was also identified in the left posterior cingulate and precuneus. Conclusions: GM volume reductions in premotor frontal regions may underlie the motor difficulties characteristic of DCD. It is possible that intervention approaches targeting motor planning, attention, and executive functioning processes associated with the regions of reduced GM volume may result in functional improvements in children with DCD

Mirror neuron system activation in children with developmental coordination disorder: A replication functional MRI study

Background: It has been hypothesised that abnormal functioning of the mirror neuron system (MNS) may lead to deficits in imitation and the internal representation of movement, potentially contributing to the motor impairments associated with developmental coordination disorder (DCD). Aims: Using fMRI, this study examined brain activation patterns in children with and without DCD on a finger adduction/abduction task during four MNS activation states: observation; motor imagery; execution; and imitation. Methods and procedures: Nineteen boys (8.25–12.75 years) participated, including 10 children with DCD (≤16th percentile on MABC-2; no ADHD/ASD), and nine typically developing controls (≥25th percentile on MABC-2). Outcomes and results: Even though children with DCD displayed deficits behaviourally on imitation (Sensory Integration & Praxis Test Subtests) and motor imagery assessments prior to scanning, no differences in MNS activation were seen between the DCD and control groups at a neurological level, with both groups activating mirror regions effectively across conditions. Small clusters of decreased activation during imitation were identified in non-mirror regions in the DCD group, including the thalamus, caudate, and posterior cingulate − regions involved in motor planning and attentional processes. Conclusions and implications: The results of this study do not provide support for the MNS dysfunction theory as a possible causal mechanism for DCD. Further research to explore attentional and motor planning processes and how they may interact at a network level may enhance our understanding of this complex disorder

The effect of multidisciplinary rehabilitation on brain structure and cognition in Huntington\u27s disease: An exploratory study

Background: There is a wealth of evidence detailing gray matter degeneration and loss of cognitive function over time in individuals with Huntington\u27s disease (HD). Efforts to attenuate disease-related brain and cognitive changes have been unsuccessful to date. Multidisciplinary rehabilitation, comprising motor and cognitive intervention, has been shown to positively impact on functional capacity, depression, quality of life and some aspects of cognition in individuals with HD. This exploratory study aimed to evaluate, for the first time, whether multidisciplinary rehabilitation can slow further deterioration of disease-related brain changes and related cognitive deficits in individuals with manifest HD. Methods: Fifteen participants who manifest HD undertook a multidisciplinary rehabilitation intervention spanning 9 months. The intervention consisted of once-weekly supervised clinical exercise, thrice-weekly self-directed home based exercise and fortnightly occupational therapy. Participants were assessed using MR imaging and validated cognitive measures at baseline and after 9 months. Results: Participants displayed significantly increased gray matter volume in the right caudate and bilaterally in the dorsolateral prefrontal cortex after 9 months of multidisciplinary rehabilitation. Volumetric increases in gray matter were accompanied by significant improvements in verbal learning and memory (Hopkins Verbal Learning-Test). A significant association was found between gray matter volume increases in the dorsolateral prefrontal cortex and performance on verbal learning and memory. Conclusions: This study provides preliminary evidence that multidisciplinary rehabilitation positively impacts on gray matter changes and cognitive functions relating to verbal learning and memory in individuals with manifest HD. Larger controlled trials are required to confirm these preliminary findings

Efficacy of probucol on cognitive function in Alzheimer's disease: study protocol for a double-blind, placebo-controlled, randomised phase II trial (PIA study).

INTRODUCTION: Preclinical, clinical and epidemiological studies support the hypothesis that aberrant systemic metabolism of amyloid beta (Aβ) in the peripheral circulation is causally related to the development of Alzheimer's disease (AD). Specifically, recent studies suggest that increased plasma concentrations of lipoprotein-Aβ compromise the brain microvasculature, resulting in extravasation and retention of the lipoprotein-Aβ moiety. The latter results in an inflammatory response and neurodegeneration ensues. Probucol, a historic cholesterol-lowering drug, has been shown in murine models to suppress lipoprotein-Aβ secretion, concomitant with maintaining blood-brain-barrier function, suppressing neurovascular inflammation and supporting cognitive function. This protocol details the probucol in Alzheimer's study, a drug intervention trial investigating if probucol has potential to attenuate cognitive decline, delay brain atrophy and reduce cerebral amyloid burden in patients with mild-to-moderate AD. METHODS AND ANALYSIS: The study is a phase II, randomised, placebo-controlled, double-blind single-site clinical trial held in Perth, Australia. The target sample is 314 participants with mild-to-moderate AD. Participants will be recruited and randomised (1:1) to a 104-week intervention consisting of placebo induction for 2 weeks followed by 102 weeks of probucol (Lorelco) or placebo. The primary outcome is changed in cognitive performance determined via the Alzheimer's Disease Assessment Scales-Cognitive Subscale test between baseline and 104 weeks. Secondary outcomes measures will be the change in brain structure and function, cerebral amyloid load, quality of life, and the safety and tolerability of Lorelco, after a 104week intervention. ETHICS AND DISSEMINATION: The study has been approved by the Bellberry Limited Human Research Ethics Committee (approval number: HREC2019-11-1063; Version 4, 6 October 2021). Informed consent will be obtained from participants prior to any study procedures being performed. The investigator group will disseminate study findings through peer-reviewed publications, key conferences and local stakeholder events. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry (ACTRN12621000726853)

Cortical functioning in children with developmental coordination disorder:a motor overflow study

This study examined brain activation in children with developmental coordination disorder (DCD) to reveal areas that may contribute to poor movement execution and/or abundant motor overflow. Using functional magnetic resonance imaging, 13 boys with DCD (mean age = 9.6 years ±0.8) and 13 typically developing controls (mean age = 9.3 years ±0.6) were scanned performing two tasks (finger sequencing and hand clenching) with their dominant hand, while a four-finger motion sensor recorded contralateral motor overflow on their non-dominant hand. Despite displaying increased motor overflow on both functional tasks during scanning, there were no obvious activation deficits in the DCD group to explain the abundant motor overflow seen. However, children with DCD were found to display decreased activation in the left superior frontal gyrus on the finger-sequencing task, an area which plays an integral role in executive and spatially oriented processing. Decreased activation was also seen in the left inferior frontal gyrus, an area typically active during the observation and imitation of hand movements. Finally, increased activation in the right postcentral gyrus was seen in children with DCD, which may reflect increased reliance on somatosensory information during the execution of complex fine motor tasks

Early postoperative MRI overestimates residual tumour after resection of gliomas with no or minimal enhancement

Standards for residual tumour measurement after resection of gliomas with no or minimal enhancement have not yet been established. In this study residual volumes on early and late postoperative T2-/FLAIR-weighted MRI are compared. A retrospective cohort included 58 consecutive glioma patients with no or minimal preoperative gadolinium enhancement. Inclusion criteria were first-time resection between 2007 and 2009 with a T2-/FLAIR-based target volume and availability of preoperative, early (<48 h) and late (1-7 months) postoperative MRI. The volumes of non-enhancing T2/FLAIR tissue and diffusion restriction areas were measured. Residual tumour volumes were 22% smaller on late postoperative compared with early postoperative T2-weighted MRI and 49% smaller for FLAIR-weighted imaging. Postoperative restricted diffusion volume correlated with the difference between early and late postoperative FLAIR volumes and with the difference between T2 and FLAIR volumes on early postoperative MRI. We observed a systematic and substantial overestimation of residual non-enhancing volume on MRI within 48 h of resection compared with months postoperatively, in particular for FLAIR imaging. Resection-induced ischaemia contributes to this overestimation, as may other operative effects. This indicates that early postoperative MRI is less reliable to determine the extent of non-enhancing residual glioma and restricted diffusion volumes are imperativ