Age-matched Control Subjects Research Articles

Relative dilatation of left ventricle and left atrium in patients with Parkinson disease

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): This study was supported by Czech Health Research Council AZV NU21-04-00445 and by the European Regional Development Fund - project ENOCH (No. CZ.02.1.01/0.0/0.0/16_019/0000868) Introduction Morbus Parkinson (MP) is the second most common neurodegenerative disease that progressively affects the nervous system. Accompanying heart problems may include mainly cardiovascular autonomic dysfunction. So far, very little is known about structural and functional cardiac changes in patients with MP. Purpose This pilot study aimed to analyse left ventricular (LV) and left atrial (LA) function and volumes using cardiovascular magnetic resonance (CMR). Methods In this study, 37 patients with MP (mean age 59,0 ± 8,0 years) without a history of cardiac disease or symptoms were compared to 37 sex- and age-matched control subjects without any heart disease history (mean age 54,5 ± 11,4 years). All patients underwent CMR examination at 1,5 MR scanner, including cine images for assessment of LV and LA volumetric and functional parameters. LA volumes (LAV) were measured at LV end-systole (maximum LAV - LAVmax), before the atrial contraction (pre-atrial contraction volume - LAVpac), and at late LV diastole (minimum LAV - LAVmin) and indexed (I) to the body surface area. LA strains were analysed for all LA phases: reservoir strain (LSr), conduit strain (LScd), and contractile strain (LSct). Descriptive statistics are reported as the mean (SD) or median (IQR) for normally and non-normally distributed continuous variables. All the p-values were adjusted using a false discovery rate for multiple comparisons. Results MP patients had normal global and regional systolic LV function – LV ejection fraction (EF) 65,9 ± 6,8% vs 68,9 ± 7,0% (p = NS). On the contrary, all indexed LV volumes were significantly higher in comparison to controls: LV end-diastolic volume index was 67,3 ± 12,1 ml/m2 vs 58,3 ± 11,7 ml/m2 (p = 0,013), LV end-systolic volume index was 22,0 (17,8 to 27,5) ml/m2 vs 18,9 (13,2 to 21,9) ml/m2 (p = 0,027), and LV stroke volume index was 43,8 ± 7,2 ml/m2 vs 39,8 ± 6,3 ml/m2 (p = 0,035). Similarly, indexed LAVmax and LAVpac were also relatively increased: LAVImax 42,7 ± 9,0 ml/m2 vs 35,7 ± 10,3 ml/m2 (p = 0,014), LAVIpac 29,8 ± 7,1 vs 23,8 ± 7,6 ml/m2 (p = 0,012). LAVImin was similar in both groups: 17,3 ± 5,5 ml/m2 vs 14,3 ± 6,7 ml/m2 (p = NS). LA strains were slightly lower in the MP cohort during the reservoir and conduit phase, and slightly higher in the contractile one. However, the difference did not reach statistical significance in any phase. Conclusion Patients with Parkinson´s disease have enlarged LV and LA compared to controls.

Netrin-1 controls inflammation in response to ischemic stroke through altering microglia phenotype.

The current approaches that are used to treat ischemic stroke suffer from poor targeting, lack of effectiveness, and potential off-target effects, necessitating the development of new therapeutic strategies to enhance neuronal cell survival and regeneration. This study aimed to investigate the role of microglial Netrin-1 in ischemic stroke, a topic that has not been fully understood. Netrin-1 levels and its primary receptor expressions were investigated in cerebral microglia from acute ischemic stroke patients and age-matched control subjects. A public database (GEO148350), which supplied RNAseq results for rat cerebral microglia in a middle cerebral artery occlusion (MCAO) model, was analyzed to assess the expression of Netrin-1, its major receptors, and genes related to macrophage function. A microglia-specific gene targeting approach and a delivery system allowing for crossing the blood-brain barrier were applied in a mouse model for ischemic stroke to investigate the role of microglial Netrin-1. Netrin-1 receptor signaling in microglia was observed and the effects on microglial phenotype, apoptosis, and migration were analyzed. Across human patients, rat and mouse models, activation of Netrin-1 receptor signaling was mainly conducted via its receptor UNC5a in microglia, which resulted in a shift in microglial phenotype towards an anti-inflammatory or M2-like state, leading to a reduction in apoptosis and migration of microglia. Netrin-1-induced phenotypic change in microglia exerted protective effects on neuronal cells in vivo during ischemic stroke. Our study highlights the potential of targeting Netrin-1 and its receptors as a promising therapeutic strategy for promoting post-ischemic survival and functional recovery.

Blinking Parameters Do Not Normalize After Botulinum Toxin Therapy in Blepharospasm and Hemifacial Spasm Patients.

Little is known regarding changes induced by botulinum toxin injections on blinking parameters in blepharospasm (BSP) and hemifacial spasm (HFS) patients. The purpose of this study was to investigate objective changes induced by botulinum toxin (BoNT) injections on blinking parameters in BSP and HFS patients. Thirty-seven patients with BSP and HFS were evaluated before and 30 days after receiving onabotulinumtoxinA injections. Twelve age-matched control subjects were also assessed. Pretreatment and post-treatment parameters were assessed and compared with normal controls. A high-speed camera and microlight-emitting diodes were used to register the blinking in patients and control groups. Outcomes were blinking frequency, amplitude, and maximum velocity of eyelid closure. BoNT injections led to a significant reduction in all parameters, compared with baseline, in BSP and on the affected side in HFS, respectively: 22% (P < 0.001) and 20% (P = 0.015) in amplitude; 21% (P = 0.04) and 39% in frequency (P = 0.002); and 41% (P < 0.001) and 26% (P = 0.005) in maximum closing velocity. Blinking amplitude (P = 0.017 and P = 0.019) and velocity (P < 0.001 for both groups) were significantly lower at 30 days on BSP and on the affected HFS side, when compared with controls. BSP and HFS patients presented a significantly lower velocity of eyelid closure, even before BoNT, compared with controls (P = 0.004. and P < 0.001, respectively). Although blinking frequency became close to normal, amplitude and velocity after BoNT applications were significantly lower in BSP and on the affected side of HFS patients when compared with age-matched normal controls, demonstrating that blinking parameters do not normalize after treatment. The velocity of eyelid closure was shown to be significantly lower, even before BoNT treatment, when compared with control subjects.

Longitudinal Changes in Ventricular Mechanics in Adolescents After the Fontan Operation

Ventricular dysfunction is a significant clinical challenge in the long-term follow-up of patients with single-ventricle (SV) physiology. Ventricular function and myocardial mechanics can be studied using speckle-tracking echocardiography, which provides information on myocardial deformation. Limited information is available on serial changes in SV myocardial mechanics after the Fontan operation. The aim of this study was to describe serial changes in myocardial mechanics in children after the Fontan operation and the relationship of these changes with myocardial fibrosis markers as obtained by cardiac magnetic resonance and exercise performance parameters. The authors hypothesized that ventricular mechanics decline in patients with SVs over time and are associated with increased myocardial fibrosis and reduced exercise performance. A single-center retrospective cohort study including adolescents after the Fontan operation was conducted. Ventricular strain and torsion were assessed using speckle-tracking echocardiography. Cardiac magnetic resonance and cardiopulmonary exercise testing data closest to the latest echocardiographic examinations were performed. The most recent follow-up echocardiographic and cardiac magnetic resonance data were compared with those from sex- and age-matched control subjects and with individual patients' early post-Fontan data. Fifty patients with SVs (31 left ventricle, 13 right ventricle [RV], and six codominant) were included. Median time at follow-up echocardiography from the time of Fontan was 12.8years (interquartile range [IQR], 10.6 to 16.6years). Compared with early post-Fontan echocardiography, follow-up assessment showed reduced global longitudinal strain (-17.5% [IQR, -14.5% to -19.5%] vs -19.8% [IQR, -16.0% to -21.7%], P=.01], circumferential strain (-15.7% [IQR, -11.4% to -18.7%] vs -18.9% [IQR, -15.2% to -25.0%], P=.009), and torsion (1.28°/cm [IQR, 0.51°/cm to 1.74°/cm] vs 1.72°/cm [IQR, 0.92°/cm to 2.34°/cm], P=.02), with decreased apical rotation but no significant change in basal rotation. Single RVs had lower torsion compared with single left ventricles (1.04°/cm [IQR, 0.12°/cm to 2.20°/cm] vs 1.25°/cm [IQR, 0.25°/cm to 2.51°/cm], P=.01). T1 values were higher in patients with SV compared with control subjects (1,009±36 vs 958±40msec, P=.004) and in those with single RVs compared with single left ventricles (1,023±19 vs 1,006±17msec, P=.02). T1 was correlated with circumferential strain (r=0.59, P=.04) and inversely correlated with O2 saturation (r=-0.67, P<.001) and torsion (r=-0.71, P=.02). Peak oxygen consumption was correlated with torsion (r=0.52, P=.001) and untwist rates (r=0.23, P=.03). After the Fontan procedures, there is a progressive decrease in myocardial deformation parameters. The progressive decrease in SV torsion is related to a decrease in apical rotation, which is more pronounced in single RVs. Decreased torsion is associated with increased markers of myocardial fibrosis and lower maximal exercise capacity. Torsional mechanics may be an important parameter to monitor after Fontan palliation, but further prognostic information is required.

Morphological and functional assessment of the tear film and meibomian glands in keratoconus.

To evaluate morphological and functional state of the meibomian glands (MG) in keratoconus patients. One hundred eyes of 100 keratoconus patients and 100 eyes of 100 age-matched control subjects were included into this study. Ocular Surface Disease Index (OSDI) scores, non-invasive break up time (NIBUT), findings of meibography, staining with fluorescein of the ocular surface, tear film break-up time (TBUT), and Schirmer I test were documented in all patients' eyes and control eyes and were compared between the groups . The mean TBUT and NIBUT were significantly lower, corneal staining and OSDI scores were statistically greater in the keratoconus group (p < 0.05). The mean meiboscore, partial gland, gland dropout and gland thickening scores for upper/lower eyelids were significantly greater in keratoconus patients than controls (p < 0.05). The NIBUT measurements significantly correlated with MG loss in upper/lower eyelids (p < 0.05). The severity of keratoconus seemed to correlate with meiboscore, partial gland, gland thickening scores in upper/lower eyelids. Our data suggests that corneal ectasia in keratoconus is related with alterations in ocular surface, tear film function and MG morphology. Early screening and treatment of MG dysfunction may improve ocular surface quality and allow better disease management in keratoconus patients.

Preserved autophagy in cognitively intact non-demented individuals with Alzheimer's neuropathology.

Growing evidence supports that dysfunctional autophagy, the major cell mechanism responsible for removing protein aggregates and a route of clearance for Tau in healthy neurons, is a major finding in demented Alzheimer's disease (AD) patients. However, the association of autophagy with maintenance of cognitive integrity in resilient individuals who have AD neuropathology but remain non-demented (NDAN) has not been evaluated. Using post mortem brain samples from age-matched healthy control, AD, and NDAN subjects, we evaluated autophagy in relation to Tau pathology using Western blot, immunofluorescence and RNA-seq. Compared to AD patients, NDAN subjects had preserved autophagy and reduced tauopathy. Furthermore, expression of autophagy genes and AD-related proteins were significantly associated in NDAN compared to AD and control subjects. Our results suggest preserved autophagy is a protective mechanism that maintains cognitive integrity in NDAN individuals. This novel observation supports the potential of autophagy-inducing strategies in AD therapeutics. NDAN subjects have preserved autophagic protein levels comparable with control subjects. Compared to control subjects, NDAN subjects have significantly reduced Tau oligomers and PHF Tau phosphorylation at synapses that negatively correlate with autophagy markers. Transcription of autophagy genes strongly associates with AD-related proteins in NDAN donors.

Factual and counterfactual learning in major adolescent depressive disorder, evidence from an instrumental learning study.

The incidence of adolescent depressive disorder is globally skyrocketing in recent decades, albeit the causes and the decision deficits depression incurs has yet to be well-examined. With an instrumental learning task, the aim of the current study is to investigate the extent to which learning behavior deviates from that observed in healthy adolescent controls and track the underlying mechanistic channel for such a deviation. We recruited a group of adolescents with major depression and age-matched healthy control subjects to carry out the learning task with either gain or loss outcome and applied a reinforcement learning model that dissociates valence (positive v. negative) of reward prediction error and selection (chosen v. unchosen). The results demonstrated that adolescent depressive patients performed significantly less well than the control group. Learning rates suggested that the optimistic bias that overall characterizes healthy adolescent subjects was absent for the depressive adolescent patients. Moreover, depressed adolescents exhibited an increased pessimistic bias for the counterfactual outcome. Lastly, individual difference analysis suggested that these observed biases, which significantly deviated from that observed in normal controls, were linked with the severity of depressive symoptoms as measured by HAMD scores. By leveraging an incentivized instrumental learning task with computational modeling within a reinforcement learning framework, the current study reveals a mechanistic decision-making deficit in adolescent depressive disorder. These findings, which have implications for the identification of behavioral markers in depression, could support the clinical evaluation, including both diagnosis and prognosis of this disorder.

Olfactory bulb volume in cochlear implant candidates as compared to age-matched control subjects: A potential marker of cognitive function for auditory information processing.

To evaluate magnetic resonance imaging (MRI)-based olfactory bulb (OB) volumes in cochlear implant (CI) candidates with sensorineural hearing loss as compared to age-matched control subjects with normal hearing. A total of 31 pediatric CI candidates (mean±SD age: 7.0±2.5 years, 51.6% were boys) with sensorineural hearing loss and 35 age-matched control subjects (mean±SD age: 7.1±2.5 years, 54.3% were boys) with normal hearing were included in this study. Data on demographic characteristics (age, gender) and right and left OB volume (mm3) on MRI using planimetric contouring method were recorded in patients and control groups. Median (min-max) values for right OB volume (80(50-120) vs. 90(50-160) mm3, p=0.006) and left OB volume (70(50-120) vs. 90(50-170) mm3, p=0.007) were significantly lower in CI candidates vs. controls, regardless of the gender and age. No significant difference was noted between right and left OB volume in CI candidate and control groups. Hearing loss subgroups of CI candidates including hereditary familial (n=8), hereditary non-familial (n=14) and mixed syndromic (9) subgroups were also similar in terms of patient demographics and OB volumes. There was a tendency for having lower left OB volume (60(50-120) vs. 80(60-110) mm3) in girls vs. boys in the CI candidate group, along with a tendency for lower left and right OB volume in candidates vs. controls, particularly at age 11 (median 120 vs. 80mm3 and 120 vs. 60mm3, respectively). No significant correlation of age was noted with right and left OB volume overall and in the study groups. In conclusion, our findings revealed lower left and right OB volumes in CI candidates compared to control subjects, regardless of age and gender, indicating the presence of baseline olfactory dysfunction in patients with hearing loss planned to undergo CI. Accordingly, MRI-based measurement of OB volume in the pre-surgical workup of CI candidates may serve as a marker of cognitive function enabling auditory information processing that may also correlate with post-operative CI outcomes.

Corneal confocal microscopy identifies corneal nerve fiber loss in patients with migraine.

Migraine affects >1 billion people but its pathophysiology remains poorly understood. Alterations in the trigeminovascular system play an important role. We have compared corneal nerve morphology in patients with migraine to healthy controls. Sixty patients with episodic (n = 32) or chronic (n = 28) migraine and 20 age-matched healthy control subjects were studied cross-sectionally. Their migraine characteristics and signs and symptoms of dry eyes were assessed. Manual and automated quantification of corneal nerves was undertaken by corneal confocal microscopy. In patients with migraine compared to controls, manual corneal nerve fiber density (P < 0.001), branch density (P = 0.015) and length (P < 0.001); and automated corneal nerve fiber density (P < 0.001), branch density (P < 0.001), length (P < 0.001), total branch density (P < 0.001), nerve fiber area (P < 0.001), nerve fiber width (P = 0.045) and fractal dimension (P < 0.001) were lower. Automated corneal nerve fiber density was higher in patients with episodic migraine and aura (P = 0.010); and fractal dimension (P = 0.029) was lower in patients with more headache days in the last three months. Automated corneal nerve fiber density predicted a significant amount of the observed variance in pain intensity (adjusted r2 = 0.14, partial r = -0.37, P = 0.004) in patients with migraine. Corneal confocal microscopy reveals corneal nerve loss in patients with migraine. It may serve as an objective imaging biomarker of neurodegeneration in migraine.

Muscle synergies in Parkinson’s disease before and after the deep brain stimulation of the bilateral subthalamic nucleus

The aim of this study is to quantitatively assess motor control changes in Parkinson’s disease (PD) patients after bilateral deep brain stimulation of the subthalamic nucleus (STN-DBS), based on a novel muscle synergy evaluation approach. A group of 20 PD patients evaluated at baseline (before surgery, T0), at 3 months (T1), and at 12 months (T2) after STN-DBS surgery, as well as a group of 20 age-matched healthy control subjects, underwent an instrumented gait analysis, including surface electromyography recordings from 12 muscles. A smaller number of muscle synergies was found in PD patients (4 muscle synergies, at each time point) compared to control subjects (5 muscle synergies). The neuromuscular robustness of PD patients—that at T0 was smaller with respect to controls (PD T0: 69.3 ± 2.2% vs. Controls: 77.6 ± 1.8%, p = 0.004)—increased at T1 (75.8 ± 1.8%), becoming not different from that of controls at T2 (77.5 ± 1.9%). The muscle synergies analysis may offer clinicians new knowledge on the neuromuscular structure underlying PD motor types of behavior and how they can improve after electroceutical STN-DBS therapy.

Amygdala hyperactivation relates to eating behaviour: a potential indicator of food addiction in Prader-Willi syndrome.

Prader-Willi syndrome is a rare neurodevelopmental genetic disorder characterized by various endocrine, cognitive and behavioural problems. The symptoms include an obsession for food and reduced satiety, which leads to hyperphagia and morbid obesity. Neuropsychological studies have reported that Prader-Willi patients display altered social interactions with a specific weakness in interpreting social information and responding to them, a symptom close to that observed in autism spectrum disorders. In the present case-control study, we hypothesized that brain regions associated with compulsive eating behaviour would be abnormally activated by food-related odours in Prader-Willi syndrome, as these can stimulate the appetite and induce hunger-related behaviour. We conducted a brain imaging study using the olfactory modality because odours have a high-hedonic valence and can cause stronger emotional reactions than other modalities. Further, the olfactory system is also intimately associated with the endocrine regulation of energy balance and is the most appropriate modality for studies of Prader-Willi syndrome. A total of 16 Prader-Willi participants were recruited for this study, which is a significant achievement given the low incidence rate of this rare disease. The second group of 11 control age-matched subjects also participated in the brain imaging study. In the MRI scanner, using an MRI-compatible olfactometer during 56 block sessions, we randomly presented two odours (tulip and caramel), which have different hedonic valence and a different capacity to arouse hunger-related behaviour. Our results demonstrate that Prader-Willi participants have abnormal activity in the brain reward system that regulates eating behaviour. Indeed, we found that these patients had right amygdala activity up to five times higher in response to a food odour (caramel) compared with the tulip odour. In contrast, age-matched control participants had similar activity levels in response to both odours. The amygdala activity levels were found to be associated with the severity of the hyperphagia in Prader-Willi patients. Our results provide evidence for functional alteration of the right amygdala in Prader-Willi syndrome, which is part of the brain network involved in food addiction modulated by the ghrelin and oxytocin systems, which may drive the hyperphagia. Our study provides important new insights into the functioning of emotion-related brain circuits and pathology, and it is one of the few to explore the dysfunction of the neural circuits involved in emotion and addiction in Prader-Willi syndrome. It suggests new directions for the exploration and remediation of addictive behaviours.

Serum levels of ceruloplasmin and magnesium in polycystic ovarian syndrome: a cross sectional study

Aim: Polycystic ovarian syndrome (PCOS) is the most common endocrine condition, affecting 5–7% of reproductive-age women worldwide. It is associated with low-grade chronic inflammation, insulin resistance, and metabolic syndrome. Studies have shown ceruloplasmin (Cp) as an independent risk factor for metabolic syndrome and magnesium (Mg), which is required for proper glucose utilization. This study aimed to compare the serum Mg and Cp in PCOS and healthy women and correlate their levels with changes in biochemical, hormonal, and gynaecological aspects of PCOS. Methods: The study comprised 98 women diagnosed with PCOS using the Rotterdam criteria and 75 age-matched healthy control subjects. The level of serum Cp and Mg were determined using Somani Ambade colorimetric method and methylthymol blue method respectively. Results: Serum Cp was higher and Mg levels were lower significantly in PCOS patients in comparison with controls. Mg was inversely correlated with fasting blood glucose and directly correlated with follicle-stimulating hormone (FSH). Cp was inversely correlated with prolactin and thyroid-stimulating hormone. Multiple regression analysis revealed that Cp correlates with both the level of luteinizing hormone (LH) and LH/FSH ratio, whereas serum Mg did not have a significant correlation with any of the clinical variables. Logistic regression analysis revealed elevated Cp, antral follicle count (AFC), body mass index (BMI), weight, and irregular menses increase the risk of developing PCOS, whereas Mg was not a risk factor. However, high LH and LH/FSH ratios were risk factors for hypomagnesemia. In conclusion, serum Cp levels in PCOS may be evaluated as an additional risk factor in association with AFC, BMI, weight, and irregular menses. Conclusions: Mg deficiency and high Cp play an important etiological role in PCOS pathogenesis. Thus, research evaluating dietary interventions and supplementation is warranted.

Associations between anxiety, depression with migraine, and migraine-related burdens.

Anxiety and depression are the most common psychiatric comorbidities in migraine, but their impact on the risk of developing migraine and their gender and age differences are unclear, and research on their associations with migraine-related burdens are limited. To systematically explore the association between anxiety and depression with migraine and migraine-related burdens, including the risk of developing migraine, as well as migraine frequency, severity, disability, headache impact, quality of life and sleep quality. A total of 170 migraineurs and 85 sex-and age-matched healthy control subjects were recruited consecutively for this study. Anxiety and depression were assessed using Zung's Self-rating Anxiety Scale (SAS) and Self-rating Depression Scale (SDS), respectively. Logistic regression and linear regression analyses were used to explore the associations between anxiety and depression with migraine and its burdens. The receiver operating characteristic (ROC) curve was used to evaluate the predictive value of SAS score and SDS score on migraine and its severe burdens. After adjusting for confounders, anxiety and depression remained significantly associated with an increased risk of developing migraine, with odds ratios of 5.186 (95% CI:1.755-15.322) and 3.147 (95% CI:1.387-7.141), respectively. Meanwhile, there were significant additive interactions between the association of anxiety and depression with the risk of developing migraine in gender and age (P for interaction <0.05), and the stronger correlations were found in participants with an age ≤ 36 years old and females. In addition, anxiety and depression were significantly independently associated with the migraine frequency, severity, disability, headache impact, quality of life, and sleep quality in migraine patients (P trend <0.05). The area under the ROC curve (AUC) of SAS score in predicting developing migraine was significantly higher than that of SDS score [0.749 (95% CI: 0.691-0.801) vs. 0.633 (95% CI: 0.571-0.692), p < 0.0001]. Anxiety and depression were significantly independently associated with the increased risk of migraine and migraine-related burdens. Enhanced assessment of SAS score and SDS score is of great clinical value for the early prevention and treatment of migraine and its burdens.

Imaging regional histone deacetylase expression in dementia with Lewy bodies with [11C]Martinostat (P13-6.008)

<h3>Objective:</h3> To image brain histone deacetylase (HDAC) expression using [¹¹C]Martinostat positron emission tomography (PET) in living participants with dementia with Lewy bodies (DLB). <h3>Background:</h3> Epigenetic modifications via HDACs and other mechanisms regulate transcription of specific genes in response to a cell’s environment or exposure, and epigenetic changes have been observed in postmortem brain tissue in Lewy body diseases. However, whether HDAC changes arise early in disease or only as a late phenomenon, and whether regional brain HDAC expression relates to the clinical or pathologic features of the disease remain uncertain. <h3>Design/Methods:</h3> Seven subjects with DLB and 17 age-matched healthy control (HC) subjects provided informed consent to participate. Participants underwent cognitive, motor, and neuropsychiatric evaluation followed by simultaneous MR and PET imaging with [¹¹C]Martinostat, a radioligand developed at the Massachusetts General Hospital (MGH) Martinos Center for Biomedical Imaging that binds class I HDACs with high affinity and selectivity. Data were reconstructed and standardized uptake value ratios computed using a global reference. A whole-brain voxelwise analysis was followed by region of interest-based analysis. <h3>Results:</h3> Compared to HC subjects, [¹¹C]Martinostat uptake in DLB was increased in regions enriched for Lewy body pathology, including the brainstem, medial temporal lobe, and anterior cingulate. Increased uptake was also observed in regions associated with motor function, including the striatum, motor cortex, and cerebellum. [¹¹C]Martinostat uptake was decreased in parietal cortex. <h3>Conclusions:</h3> These preliminary findings in living participants with DLB identify abnormal class I HDAC expression in regions associated with Lewy body pathology, motor circuitry, and cognition. They set the stage for planned comparisons with antemortem Parkinson’s disease (PD) and with postmortem regional HDAC expression in PD and DLB. <b>Disclosure:</b> The institution of Dr. Goodheart has received research support from American Academy of Neurology. Mr. Yoo has nothing to disclose. Ms. Striar has nothing to disclose. Ms. Quan has nothing to disclose. Prof. Wey has nothing to disclose. Dr. Wang has nothing to disclose. Dr. Gomperts has received personal compensation in the range of $0-$499 for serving as a Consultant for EIP. Dr. Gomperts has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Jannsen. The institution of Dr. Gomperts has received research support from NIH. The institution of Dr. Gomperts has received research support from LBDA. The institution of Dr. Gomperts has received research support from DOD/CDMRP. The institution of Dr. Gomperts has received research support from FFFPRI. The institution of Dr. Gomperts has received research support from NIH. The institution of Dr. Gomperts has received research support from MJFF. The institution of Dr. Gomperts has received research support from NIH. The institution of Dr. Gomperts has received research support from NIH. The institution of Dr. Gomperts has received research support from MJFF. The institution of Dr. Gomperts has received research support from NIH. The institution of Dr. Gomperts has received research support from NIH.

Impact of One-Piece Fronto-Orbital Distraction Osteogenesis on Orbital Morphology and Strabismus Development in Unilateral Craniosynostosis.

Unicoronal craniosynostosis (UCS) is associated with orbital dysmorphologies that underlie ophthalmologic dysfunctions, such as strabismus. This study aimed to assess orbital dysmorphology in patients with UCS and how it changes after fronto-orbital distraction osteogenesis (FODO), and to analyze the features of new-onset strabismus. A retrospective analysis was conducted on 19 patients with UCS who underwent FODO between May of 2008 and November of 2020. Ophthalmologic records and computed tomographic scans were reviewed. Seven parameters, including width, height, volume, and four-direction orbital angles were evaluated in patients with UCS and compared with those of age-matched control subjects. The superolateral angle and vertical angle of the ipsilateral orbit and the superomedial angle (SMA) of the contralateral orbit were more obtuse than those of the controls. Following FODO, the ipsilateral superolateral angle was decreased from 69.2 ± 5.4 degrees to 59.1 ± 4.2 degrees ( P = 0.001), and the contralateral SMA was decreased from 64.8 ± 5.8 degrees to 60.2 ± 6.0 degrees ( P = 0.003). Four of the 17 patients without strabismus in the preoperative period developed strabismus, and the horizontal type was the most common. Logistic regression analysis demonstrated a significant association between new-onset strabismus and SMA difference between both orbits (OR, 1.39; P = 0.041). Orbital dysmorphology in the UCS is bilateral, and the orbital roofs are dysmorphic. The bilateral orbital roofs are lifted toward the fused coronal suture and can be improved after FODO. Horizontal strabismus, such as esotropia and exotropia, is common after FODO, and superomedial orbital roof asymmetry may play a role in its development. Therapeutic, IV.

Abstract 788: Novel multiplex methylation-specific qPCR strategy for early CRC detection

Abstract Colorectal cancer (CRC) can be cured if detected early. Analysis of abnormalities in cfDNA methylation is an emerging and powerful strategy for early cancer detection. Recently, targeted methylation NGS methods have shown encouraging performance in CRC detection, but their high cost and complicated workflow can be challenging for many clinical settings. At the same time, the alternative, single methylation biomarker PCR assays, demonstrate limited sensitivity and specificity. An accurate, accessible and affordable assay ideal for clinical applications requires an easily scalable set-up and a set of high quality biomarkers providing sufficient predictive power. We aim to develop an assay fulfilling the CMS definitive performance guideline of LBx CRC screening – at least 74% sensitivity and 90% specificity. Here we report the development of a novel multiplex methylation-specific qPCR (MMS-qPCR) strategy for early CRC detection. Previously, we established detailed methylation profiles of our proprietary CRC targeted methylation sequencing panel with 560 biomarkers, based on more than 500 plasma samples of both healthy controls and CRC patients of various stages. We selected 9 biomarkers that are both highly sensitive and specific for CRC. These 9 markers show methylation signatures prevalent in patients and have very low noise in healthy controls. Along with one reference gene, the 9 CRC hypermethylated biomarkers can be multiplexed and analyzed in a single methylation-specific qPCR reaction. Analytical sensitivity and specificity were determined using a model system where hypermethylated DNA molecules were spiked into normal cell free DNA background at various percentages. With 10 ng of input, we can detect a single copy of the hypermethylated genome, achieving 0.006% limit of detection. Plasma samples from 10 stage I and 11 stage II CRC patients as well as 104 age-matched control subjects were subjected to the PCR analysis to yield a specificity of 96% and detection rate of 50% for stage I and 81% for stage II. The total turnaround time for analysis was &amp;lt;4 hours including DNA isolation, bisulfite conversion and qPCR analysis. The MMS-qPCR described here provides an accurate, accessible, and affordable liquid biopsy assay for the early detection of CRC. The same development strategy can also be applied to many other cancer types. Citation Format: Yun Bao, Heng Wang, Peter Vu, Grace Zhao, Shengrong Lin. Novel multiplex methylation-specific qPCR strategy for early CRC detection [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 788.

Right Ventricular Strain in Patients With Ductal-Dependent Tetralogy of Fallot

Right ventricular (RV) dysfunction is an independent predictor of poor outcomes in patients with tetralogy of Fallot (TOF), and global longitudinal strain (GLS) is a well-validated echocardiographic technique to measure RV function. Although trends in RV GLS have been examined in patients with TOF, they have not been studied specifically in those with ductal-dependent TOF, a group in which there is not a clear consensus on the best surgical strategy. The aim of this study was to assess the midterm trajectory of RV GLS in patients with ductal-dependent TOF, drivers of this trajectory, and differences in RV GLS between repair strategies. This was a retrospective two-center cohort study of patients with ductal-dependent TOF who underwent repair. Ductal dependence was defined as being initiated on prostaglandin therapy and/or undergoing surgical intervention on or before 30days of life. RV GLS was measured on echocardiography preoperatively, early after complete repair, and at 1 and 2years of age. RV GLS was trended over time and compared between surgical strategies and with control subjects. Mixed-effects linear regression models were used to evaluate the factors associated with changes in RV GLS over time. Forty-four patients with ductal-dependent TOF were included in the study, of whom 33 (75%) underwent primary complete repair and 11 (25%) underwent staged repair. Complete TOF repair was performed at a median of 7days in the primary-repair group and 178days in the staged-repair group. RV GLS improved over time from post-complete repair echocardiography through 2years of age (-17.4% [interquartile range, -15.5% to -18.9%] vs -21.5% [interquartile range, -18.0% to -23.3%], P<.001). However, compared with age-matched control subjects, patients had worse RV GLS at all time points. There was no difference in RV GLS between the staged and primary complete repair groups at 2-year follow-up. Shorter intensive care unit length of stay after complete repair was independently associated with improvement in RV GLS over time. Strain improved by 0.07% (95% CI, 0.01 to 0.12) for each fewer day in the intensive care unit (P=.03). RV GLS improves over time among patients with ductal-dependent TOF, though it is consistently reduced compared with control subjects, suggesting an altered deformation pattern in patients with ductal-dependent TOF. There was no difference in RV GLS between the primary- and staged-repair groups at midterm follow-up, suggesting that repair strategy is not a risk factor for worse RV strain in the mid postoperative period. A shorter complete-repair intensive care unit length of stay is associated with an improved trajectory of RV GLS.

Contraction Patterns of Post-Fontan Single Right Ventricle Versus Normal Left and Right Ventricles in Children: Insights From Principal Strain Analysis

Principal strain (PS) analysis quantifies three-dimensional myocardial deformation using three-dimensional speckle-tracking echocardiography. It defines both the amplitude and direction of the principal myocardial contraction, expressed as PS, and a perpendicular secondary strain of lower intensity. The aims of this study were to apply PS analysis to describe the contractile pattern in the single right ventricle (SRV) functioning as a systemic chamber in hypoplastic left heart syndrome, compared with the normal left ventricle (LV) and right ventricle (RV), and to compare SRV function using conventional echocardiographic evaluations. Fifty-four post-Fontan patients with hypoplastic left heart syndrome and age-matched control subjects (normal LV, n=64; normal RV, n=48) underwent computation of PS lines, ejection fraction (EF), end-diastolic volume indexed to body surface area, PS, secondary strain, circumferential strain, and longitudinal strain. The PS lines were compared between groups. Linear regressions with coefficient determination (R2) of strains, fractional area change, and tricuspid annular plane systolic excursion with EF and end-diastolic volume index were assessed in SRV. Additionally, the hypoplastic left heart syndrome cohort was equally divided into two groups with higher and lower EFs, followed by comparison of all parameters. The pattern of PS lines demonstrated a left-handed direction in the anterior free wall, a right-handed direction in the posterior free wall, and a circumferential direction in the medial wall in SRV. In contrast, in the normal LV, the principal contraction is in the circumferential direction, whereas in the normal RV, it is predominantly longitudinal. The R2 values for PS, secondary strain, and circumferential strain on EF were high (0.88, 0.72, and 0.90, respectively), whereas the R2 value for longitudinal strain was comparable with that for fractional area change (0.56 and 0.55). All parameters were independent of end-diastolic volume index. PS lines in the higher EF group showed a more circumferential orientation than in the lower EF group in SRV. PS analysis provides a unique functional map of SRV contraction. This map differs from corresponding maps of the normal LV and RV. This may be helpful in understanding the mechanisms of SRV function, although future longitudinal studies are needed.

Intrinsic brain abnormalities in chronic rhinosinusitis associated with mood and cognitive function.

Chronic rhinosinusitis (CRS) poses a risk for developing emotional and cognitive disorders. However, the neural evidence for this association is largely unclear. Resting-state functional magnetic resonance imaging (rs-fMRI) analysis can demonstrate abnormal brain activity and functional connectivity and contribute to explaining the potential pathophysiology of CRS-related mood and cognitive alterations. Chronic rhinosinusitis patients (CRS, n = 26) and gender- and age-matched healthy control subjects (HCs, n = 38) underwent resting-state functional MRI scanning. The amplitude of low-frequency fluctuations (ALFF) was calculated to observe the intrinsic brain activity. The brain region with altered ALFF was further selected as the seed for functional connectivity (FC) analysis. Correlation analysis was performed between the ALFF/FC and clinical parameters in CRS patients. Compared with HCs, CRS patients exhibited significantly increased ALFF in the left orbital superior frontal cortex and reduced connectivity in the right precuneus using the orbital superior frontal cortex as the seed region. The magnitude of the orbital superior frontal cortex increased with inflammation severity. In addition, ALFF values in the orbital superior frontal cortex were positively correlated with the hospital anxiety and depression scale (HADS) scores. The ROC curves of altered brain regions indicated great accuracy in distinguishing between CRS patients and HCs. In this study, patients with CRS showed increased neural activity in the orbital superior frontal cortex, a critical region in emotional regulation, and this region also indicated hypoconnectivity to the precuneus with a central role in modulating cognition. This study provided preliminary insights into the potential neural mechanism related to mood and cognitive dysfunctions in CRS patients.

Overshoot of the Respiratory Exchange Ratio during Recovery from Maximal Exercise Testing in Young Patients with Congenital Heart Disease

The overshoot of the respiratory exchange ratio (RER) after exercise is reduced in patients with heart failure. The present study aimed to investigate the presence of this phenomenon in young patients with congenital heart disease (CHD), who generally present reduced cardiorespiratory fitness. In this retrospective study, patients with CHD underwent a maximal cardiopulmonary exercise testing (CPET) assessing the RER recovery parameters: the RER at peak exercise, the maximum RER value reached during recovery, the magnitude of the RER overshoot and the linear slope of the RER increase after the end of the exercise. In total, 117 patients were included in this study. Of these, there were 24 healthy age-matched control subjects and 93 young patients with CHD (transposition of great arteries, Fontan procedure, aortic coarctation and tetralogy of Fallot). All patients presented a RER overshoot during recovery. Patients with CHD showed reduced aerobic capacity and cardiorespiratory efficiency during exercise, as well as a lower RER overshoot when compared to controls. RER magnitude was higher in the controls and patients with aortic coarctation when compared to those with transposition of great arteries, previous Fontan procedure, and tetralogy of Fallot. The RER magnitude was found to be correlated with the most relevant cardiorespiratory fitness and efficiency indices. The present study proposes new recovery indices for functional evaluation in patients with CHD. Thus, the RER recovery overshoots analysis should be part of routine CPET evaluation to further improve prognostic risk stratifications in patients with CHD.