Altered Iron and Microstructure in Huntington's Disease Subcortical Nuclei: Insight From 7T MRI.

BACKGROUND: Pathophysiological changes of Huntington's disease (HD) can precede symptom onset by decades. Robust imaging biomarkers are needed to monitor HD progression, especially before the clinical onset. PURPOSE: To investigate iron dysregulation and microstructure alterations in subcortical regions as HD imaging biomarkers, and to associate such alterations with motor and cognitive impairments. STUDY TYPE: Prospective. POPULATION: Fourteen individuals with premanifest HD (38.0 ± 11.0 years, 9 females; far-from-onset N = 6, near-onset N = 8), 21 manifest HD patients (49.1 ± 12.1 years, 11 females), and 33 age-matched healthy controls (43.9 ± 12.2 years, 17 females). FIELD STRENGTH/SEQUENCE: 7 T, T1 -weighted imaging, quantitative susceptibility mapping, and diffusion tensor imaging. ASSESSMENT: Volume, susceptibility, fractional anisotropy (FA), and mean diffusivity (MD) within subcortical brain structures were compared across groups, used to establish HD classification models, and correlated to clinical measures and cognitive assessments. STATISTICAL TESTS: Generalized linear model, multivariate logistic regression, receiver operating characteristics with the area under the curve (AUC), and likelihood ratio test comparing a volumetric model to one that also includes susceptibility and diffusion metrics, Wilcoxon paired signed-rank test, and Pearson's correlation. A P-value <0.05 after Benjamini-Hochberg correction was considered statistically significant. RESULTS: Significantly higher striatal susceptibility and FA were found in premanifest and manifest HD preceding atrophy, even in far-from-onset premanifest HD compared to controls (putamen susceptibility: 0.027 ± 0.022 vs. 0.018 ± 0.013 ppm; FA: 0.358 ± 0.048 vs. 0.313 ± 0.039). The model with additional susceptibility, FA, and MD features showed higher AUC compared to volume features alone when differentiating premanifest HD from HC (0.83 vs. 0.66), and manifest from premanifest HD (0.94 vs. 0.83). Higher striatal susceptibility significantly correlated with cognitive deterioration in HD (executive function: r = -0.600; socioemotional function: r = -0.486). DATA CONCLUSION: 7 T MRI revealed iron dysregulation and microstructure alterations with HD progression, which could precede volume loss, provide added value to HD differentiation, and might be associated with cognitive changes. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 2.

Comparison of quantitative susceptibility mapping methods for iron-sensitive susceptibility imaging at 7T: An evaluation in healthy subjects and patients with Huntington's disease.

Quantitative susceptibility mapping (QSM) is a promising tool for investigating iron dysregulation in neurodegenerative diseases, including Huntington's disease (HD). Many diverse methods have been proposed to generate accurate and robust QSM images. In this study, we evaluated the performance of different dipole inversion algorithms for iron-sensitive susceptibility imaging at 7T on healthy subjects of a large age range and patients with HD. We compared an iterative least-squares-based method (iLSQR), iterative methods that use regularization, single-step approaches, and deep learning-based techniques. Their performance was evaluated by comparing: (1) deviations from a multiple-orientation QSM reference; (2) visual appearance of QSM maps and the presence of artifacts; (3) susceptibility in subcortical brain regions with age; (4) regional brain susceptibility with published postmortem brain iron quantification; and (5) susceptibility in HD-affected basal ganglia regions between HD subjects and healthy controls. We found that single-step QSM methods with either total variation or total generalized variation constraints (SSTV/SSTGV) and the single-step deep learning method iQSM generally provided the best performance in terms of correlation with iron deposition and were better at differentiating between healthy controls and premanifest HD individuals, while deep learning QSM methods trained with multiple-orientation susceptibility data created QSM maps that were most similar to the multiple orientation reference and with the best visual scores.

Development of a clipped single-bag with bicarbonate replacement fluid to ensure proper mixing.

A clipped single-bag for bicarbonate replacement fluid was developed to ensure proper mixing before administering to the patient. Nonmixture can cause imbalances of electrolytes and pH, which is a key problem for the current double-bag type bicarbonate replacement fluid sets. To resolve this problem, this single bag properly mixes the solutions before use. The new bag consists of a clip that is placed in the middle to keep the two solutions separated and sealed. When the caregiver is ready to administer treatment, the bag is simply unfolded and the clip automatically detaches, releasing the fluids. Thereby, the bicarbonate fluids are effectively mixed. An optimal clip size with an outer diameter of 16 mm and thickness of 2 mm was determined using compression tests and drop tests. This bag may be a safer and more effective way to provide proper replacement fluid supply for both hemofiltration and hemodiafiltration.

Physiological adaptation to a nonpulsatile biventricular assist system.

Physiological adaptation of the recipient to a nonpulsatile biventricular assist system (NPBVAS) is not well understood. The aim of this study is to evaluate the physiological adaptation of experimental animals after NPBVAS implantation. Since May 2001, four long-term NPBVAS implant experiments in calves were performed. The blood gas and hemodynamic data were analyzed retrospectively. An additional prospective experiment was performed to confirm retrospective findings. All calves (n = 5) lived longer than 5 weeks without complication. In retrospective analysis, there was not a correlation between the O2 content and total blood flow in the pulmonary artery during the 1st postoperative week, but they began to correlate within the 2nd postoperative week. Then, there was a strong correlation after the 3rd postoperative week (r = 0.753). In the prospective experiment, O2 content related to total pulmonary flow after 2 weeks (r = 0.732) was the same as in the retrospective study. Most of the hemodynamic parameters studied became normalized after 14 days. In addition, easier controllability of the blood pumps was demonstrated after the 2nd postoperative week in all five experiments. Experimental results suggested that the native healthy heart accepted NPBVAS by reducing its cardiac output in 2 weeks. In addition, complicated control of the BPVAS was not necessary after 2 weeks of implantation. These results demonstrate the possibility of physiological adaptation to the NPBVAS being established within 2 postoperative weeks.

In vivo evaluation of the NEDO biventricular assist device with an RPM dynamic impeller suspension system.

Since 1995, the Baylor College of Medicine group has been developing the NEDO Gyro permanent implantable (PI) pump. The Gyro PI pump has achieved outstanding results up to 284 days with no thrombus formation during the left ventricular assist device (LVAD) animal experiments. However, in biventricular assist device (BVAD) animal experiments, thrombus formation did occur. An in vitro experiment showed the reason for thrombus formation was caused by the missed magnetic balance between the impeller and the actuator. On the basis of this result, the revolutions per minute (RPM) impeller suspension system was developed. Six long-term animal studies were performed in bovine models. Survival periods were 90, 80, 60, 51, 48, and 37 days, respectively. No thrombus was observed in the pumps with the exception of one right pump. In that experiment, the thrombus formation may have occurred when the pump had a low flow because of outflow kinking. In this article, the antithrombogenic effect of this RPM impeller suspension system will be discussed.

Real-time studies of the pivot bearings in the NEDO Gyro PI-710 centrifugal blood pump.

The NEDO Gyro PI-710 centrifugal pump (Gyro PI-710 pump) incorporates a double pivot bearing system of which the male pivot and female bearings are fabricated from Al2O3 ceramic and ultrahigh molecular weight polyethylene. The top female bearing is a critical component because the impeller is levitated by hydraulic force and is maintained in the top contact position. A long-term in vitro examination of the pivot bearings was conducted using a biventricular assist model. In 7 animal experiments, the depth change of the top female bearing was examined. Animal experiments up to 90 days revealed that there was no noticeable depth increase in the top female bearing. According to the in vitro study, the life of the pivot bearings of the left and right pump was estimated to be approximately 3 and 7 years, respectively. Further improvement of this pivot bearing system is currently underway.

Assessing the calf pulmonary function during a long-term biventricular assist device study with a centrifugal blood pump.

Pulmonary congestion due to inappropriate pump flow management is one major problem necessary to avoid during long-term biventricular assist device (BVAD) implantation. Our objective was to assess the effects of pulmonary arterial flow rate and flow rates of both (right and left) bypass pumps. Six healthy calves, which had been implanted with a BVAD system, were selected for this retrospective study. Pulmonary artery flows, both pump flow rates, oxygen saturation of the arterial blood, and pulmonary arterial pressures were assessed as parameters of pulmonary function as was routine clinical evaluation of respiratory rate and character and chest auscultation. The average pulmonary artery flow rate (PAF), systolic pressure of pulmonary artery (sPAP), and oxygen saturation were 148.8 ml/kg per min, 35.1 mm Hg, and 95.3%, respectively. Pulmonary dysfunction occurred in one case, in which the mean PAF, sPAP, and oxygen saturation were 169 ml/kg per min, 66.1 mm Hg, and 90.9%, respectively. The ratio for the right/left pump flow rate (R/L ratio) for the case having pulmonary dysfunction was 1.57 even though the ratio for the other cases was less than 1. Maintaining an R/L ratio less than 1 and/or PAF less than 160 ml/kg per min and PAP less than 50 mm Hg is recommended as the initial conditions to target to avoid pulmonary dysfunction during a BVAD implantation with a beating heart condition.

Titania gel reduces thrombin generation.

Titanium alloy (Ti) commonly is used for long-term blood pumps as a conventional blood contacting material. Thrombus formation in the pump, however, is still a critical problem. Once thrombin is generated on the Ti surface, it activates platelets and the coagulation cascade, leading to thrombus formation. It would be expected that an inhibition of thrombin generation on a blood-contacting surface would prevent thrombus formation. In this study, the titania gel (Ti-gel) on the surface of Ti was formed with chemical modification. The surface structure and its effects on the coagulation cascade were evaluated. Scanning electron microscopic study revealed numerous cracks on the dried surface of Ti-gel, indicating a water-enriched layer. Blood coagulation on the Ti-gel was less than that on the Ti. Generated thrombin on the Ti-gel was less than that on the Ti in both the extrinsic and intrinsic pathways. There was no statistical difference of thrombin degradation. These results suggest that coagulation cascade on the Ti surface was inhibited by the Ti-gel formation. The Ti-gel may have better antithrombogenic characteristics for blood pumps because of its antiblood-coagulation effects.

Flow visualization study to investigate the secondary flow behind the impeller in the Gyro centrifugal pump.

The Gyro permanently implantable pump consists of a sealless pump housing and an impeller supported with a double pivot bearing. The secondary vanes are attached to increase the secondary flow to avoid thrombus formation behind the impeller. Flow visualization studies using an oil film method were performed on three types of impellers: no secondary vanes, 0.5 mm height secondary vanes, and 1.0 mm height secondary vanes. Comparison studies of these impellers were performed on the surfaces of the impeller bottom and bottom housing. Regarding the surface of the impeller bottom, the impeller with no secondary vanes had the least stagnant areas around the shaft. On the other hand, the impeller having 1.0 mm height secondary vanes had the most distinguished flow lines on the bottom housing. Overall, the impeller secondary vanes with a height of 0.5 mm (current design) seemed to create the most effective secondary flow.

Centrifugal blood pump with a hydraulically-levitated impeller for a permanently implantable biventricular assist device.

A permanently implantable biventricular assist device (BVAD) system has been developed with a centrifugal pump which is activated by a hydraulically-levitated impeller. The pump impeller floats hydraulically into the top contact position; this position prevents thrombus formation by creating a washout effect at the bottom bearing area, a common stagnant region. The pump was subjected to in vitro studies using a pulsatile mock circulation loop to confirm the impeller's top contact position and the swinging motion produced by the pulsation. Eleven in vivo BVAD studies confirmed that this swinging motion eliminated blood clot formation. Twenty-one pumps im-planted for up to three months did not reveal any thrombosis in the pumps or downstream organs. One exception was a right pump which was exposed to severe low flow due to the kinking of the outflow graft by the accidental pulling of the flow meter cable. Three ninety-day BVAD studies were achieved without thrombus formation.

The balance of the impeller-driver magnet affects the antithrombogenicity in the Gyro permanently implantable pump.

The Gyro permanently implantable (PI) pump is activated magnetically when a double pivot bearing supported impeller is rotated at predetermined revolutions per minute (rpm). The male bearing shaft of the impeller is supported by the top and bottom female pivot bearing in a loosely mated fashion. The Gyro PI pump's impeller transfers to a floating condition when the rpm is increased. The design objective of the Gyro PI pump is to drive the impeller while maintaining a top contact position to prevent thrombus formation. As a left ventricular assist device (LVAD), the Gyro PI pumps achieved long-term survivals in calves without thrombus formation. However, thrombus formation occurred during a biventricular assist device (BVAD) implantation. Our hypothesis was that the impeller remaining in the bottom contact position during the BVAD experiment caused this thrombus formation. Therefore, a replica of the Gyro PI pump housing was fabricated from a transparent plastic to observe the floating conditions of the impeller. When simulating an LVAD animal experiment, the impeller was at a non-bottom contact position. However, when simulating the BVAD animal experiment, the impeller remained at the bottom contact position. This study shows that the magnet balance affects the antithrombogenicity in a Gyro PI pump.

Extracorporeal membrane oxygenator compatible with centrifugal blood pumps.

Coil-type silicone membrane oxygenators can only be used with roller blood pumps due to the resistance from the high blood flow. Therefore, during extracorporeal membrane oxygenation (ECMO) treatment, the combination of a roller pump and an oxygenator with a high blood flow resistance will induce severe hemolysis, which is a serious problem. A silicone rubber, hollow fiber membrane oxygenator that has a low blood flow resistance was developed and evaluated with centrifugal pumps. During in vitro tests, sufficient gas transfer was demonstrated with a blood flow less than 3 L/min. Blood flow resistance was 18 mm Hg at 1 L/min blood flow. This oxygenator module was combined with the Gyro C1E3 (Kyocera, Japan), and veno-arterial ECMO was established on a Dexter strain calf. An ex vivo experiment was performed for 3 days with stable gas performance and low blood flow resistance. The combination of this oxygenator and centrifugal pump may be advantageous to enhance biocompatibility and have less blood trauma characteristics.