Use of a Benzimidazole Derivative BF-188 in Fluorescence Multispectral Imaging for Selective Visualization of Tau Protein Fibrils in the Alzheimer’s Disease Brain

Purpose

Selective visualization of amyloid-β and tau protein deposits will help to understand the pathophysiology of Alzheimer’s disease (AD). Here, we introduce a novel fluorescent probe that can distinguish between these two deposits by multispectral fluorescence imaging technique.

Procedures

Fluorescence spectral analysis was performed using AD brain sections stained with novel fluorescence compounds. Competitive binding assay using [³H]-PiB was performed to evaluate the binding affinity of BF-188 for synthetic amyloid-β (Aβ) and tau fibrils.

Results

In AD brain sections, BF-188 clearly stained Aβ and tau protein deposits with different fluorescence spectra. In vitro binding assays indicated that BF-188 bound to both amyloid-β and tau fibrils with high affinity (K _i ?<?10 nM). In addition, BF-188 showed an excellent blood–brain barrier permeability in mice.

Conclusion

Multispectral imaging with BF-188 could potentially be used for selective in vivo imaging of tau deposits as well as amyloid-β in the brain.     

Diastolic Carotid Artery Longitudinal Wall Motion Is Sensitive to Both Aging and Coronary Artery Disease Status Independent of Arterial Stiffness

We investigated the ability of systolic and diastolic carotid artery longitudinal wall motion (CALM) to delineate expected differences in arterial health in individuals representing a range of both age and health status. We recruited 161 younger healthy adults (aged 24 ± 5 y), 51 older healthy adults (aged 70 ± 5 y) and 14 adults with coronary artery disease (aged 67 ± 8 y) for resting assessment of CALM and arterial stiffness. All CALM parameters were reduced in the old healthy adults and adults with coronary artery disease compared with the young healthy adults (p < 0.01), with diastolic velocity and maximum diastolic acceleration being further reduced in the adults with coronary artery disease than in the older healthy adults (p < 0.01). Diastolic CALM parameters were more strongly related to age (β range: ?0.46 to ?0.53) than systolic CALM parameters (β range: ?0.24 to ?0.44). In contrast to previous examinations of a variety of CALM parameters, diastolic CALM may provide superior promise in terms of characterizing arterial wall properties, with additional sensitivity to cardiovascular disease status.     

Time-Harmonic Ultrasound elastography of the Descending Abdominal Aorta: Initial Results

Stiffening of central large vessels is considered a key pathophysiologic factor within the cardiovascular system. Current diagnostic parameters such as pulse wave velocity (PWV) indirectly measure aortic stiffness, a hallmark of coronary diseases. The aim of the present study was to perform elastography of the proximal abdominal aorta based on externally induced time-harmonic shear waves. Experiments were performed in 30 healthy volunteers (25 young, 5 old, >50 y) and 5 patients with longstanding hypertension (PWV >10 m/s). B-Mode-guided sonographic time-harmonic elastography was used for measurement of externally induced shear waves at 30-Hz vibration frequency. Thirty-hertz shear wave amplitudes (SWAs) within the abdominal aorta were measured and displayed in real time and processed offline for differences in SWA between systole and diastole (ΔSWA). Data were analyzed using the Kruskal–Wallis test and receiver operating characteristic curve analysis. The change in SWA over the cardiac cycle was reduced significantly in all patients as assessed with ΔSWA (volunteers: mean = 10 ± 5 μm, patients: mean = 4 ± 1 μm; p < 0.001). The best separation of healthy volunteers from patients was obtained with a ΔSWA threshold of 4.7 μm, resulting in a sensitivity of 0.9 and a specificity of 1.0, with an overall area under the curve of 0.96. Time harmonic elastography of the abdominal aorta is feasible and shows promise for the exploitation of time-varying shear wave amplitudes as a diagnostic marker for aortic wall stiffening. Patients with elevated PWVs suggesting increased aortic wall stiffness were best identified by ΔSWA—a parameter that could be related to the ability of the vessel walls to distend on passages of the pulse wave.     

Associations of atherosclerosis in the descending thoracic aorta on CTA with arterial stiffness and chronic kidney disease in asymptomatic patients with diabetes mellitus

The relation between atherosclerosis in the descending thoracic aortic (DTA), arterial stiffness and chronic kidney disease (CKD) in patients with diabetes mellitus (DM) remains unclear. The current aim was to evaluate associations of DTA atherosclerosis with arterial stiffness and parameters of CKD in asymptomatic patients with DM. A total of 213 asymptomatic patients with diabetes (mean age 52 years, 56 % men) underwent cardiovascular risk assessment including multi-slice computed tomography (for non-invasive coronary angiography, from which DTA atherosclerosis can be derived), non-invasive assessment of arterial stiffness with applanation tonometry and assessment of renal function. Measurements of DTA atherosclerosis included assessment of DTA thickening and calcium score. Arterial stiffness was determined by the carotid-femoral pulse wave velocity (PWV), parameters of CKD included estimated glomerular filtration rate (eGFR) and urinary albumin-creatinine ratio (UACR). DTA atherosclerosis was present in 180 (84 %) patients. Patients with DTA atherosclerosis had increased arterial stiffness, lower eGFR and higher UACR values. After multivariate correction, DTA calcium score was independently associated with PWV (β = 0.18, p = 0.04). Furthermore, both DTA maximal wall thickness and DTA calcium score were independently associated with eGFR (β = ?7.37, p < 0.001 and β = ?1.99, p < 0.003, respectively), but not with UACR. The increase in arterial stiffness by atherosclerosis seemed to be mediated by arterial calcification, while the DTA calcium score was independently associated with arterial stiffness, but not DTA maximal wall thickness. Furthermore, parameters of CKD in patients with DM had a distinct relationship with DTA atherosclerosis: DTA atherosclerosis was associated with eGFR but not with UACR.     

Regional assessment of carotid artery pulse wave velocity using compressed sensing accelerated high temporal resolution 2D CINE phase contrast cardiovascular magnetic resonance

Background

Cardiovascular magnetic resonance (CMR) allows for non-invasive assessment of arterial stiffness by means of measuring pulse wave velocity (PWV). PWV can be calculated from the time shift between two time-resolved flow curves acquired at two locations within an arterial segment. These flow curves can be derived from two-dimensional CINE phase contrast CMR (2D CINE PC CMR). While CMR-derived PWV measurements have proven to be accurate for the aorta, this is more challenging for smaller arteries such as the carotids due to the need for both high spatial and temporal resolution. In this work, we present a novel method that combines retrospectively gated 2D CINE PC CMR, high temporal binning of data and compressed sensing (CS) reconstruction to accomplish a temporal resolution of 4 ms. This enables accurate flow measurements and assessment of PWV in regional carotid artery segments.

Methods

Retrospectively gated 2D CINE PC CMR data acquired in the carotid artery was binned into cardiac frames of 4 ms length, resulting in an incoherently undersampled k_y-t-space with a mean undersampling factor of 5. The images were reconstructed by a non-linear CS reconstruction using total variation over time as a sparsifying transform. PWV values were calculated from flow curves by using foot-to-foot and cross-correlation methods. Our method was validated against ultrasound measurements in a flow phantom setup representing the carotid artery. Additionally, PWV values of two groups of 23 young (30?±?3 years, 12 [52%] women) and 10 elderly (62?±?10 years, 5 [50%] women) healthy subjects were compared using the Wilcoxon rank-sum test.

Results

Our proposed method produced very similar flow curves as those measured using ultrasound at 1 ms temporal resolution. Reliable PWV estimation proved possible for transit times down to 7.5 ms. Furthermore, significant differences in PWV values between healthy young and elderly subjects were found (4.7?±?1.0 m/s and 7.9?±?2.4 m/s, respectively; p?<?0.001) in accordance with literature.

Conclusions

Retrospectively gated 2D CINE PC CMR with CS allows for high spatiotemporal resolution flow measurements and accurate regional carotid artery PWV calculations. We foresee this technique will be valuable in protocols investigating early development of carotid atherosclerosis.

     

Relationship between left ventricular diastolic function and arterial stiffness in asymptomatic patients with diabetes mellitus

Left ventricular (LV) diastolic dysfunction and increased arterial stiffness are common in patients with diabetes mellitus (DM). However, the relation between these two pathophysiological factors remains unclear. The aim of this study was to investigate the relationship between LV diastolic function and arterial stiffness as assessed with applanation tonometry. In 142 asymptomatic patients with DM (mean age 48 years, 75 (53 %) men, 72 (51 %) patients with type 2 DM) LV diastolic function was assessed with echocardiography. Arterial stiffness was evaluated measuring the aortic pulse wave velocity (PWV) whereas wave reflection was assessed measuring central systolic blood pressure (cSBP), central pulse pressure (cPP), and augmentation index (AIx) with applanation tonometry. Mean E/A ratio, E′ and E/E′ ratio were 1.1 ± 0.3, 8.1 ± 2.3 and 9.2 ± 3.3 cm/s, respectively. Mean PWV, mean cSBP, median cPP and mean AIx were 7.9 ± 2.4 m/s, 122 ± 17 mmHg, 40 [35–51] mmHg and 17.9 ± 12.1 %, respectively. PWV was independently associated with LV diastolic dysfunction grade (β = 0.76, p = 0.03). In contrast, measures of wave reflection, cPP, cSBP and AIx were independently related with E/A ratio, but not with the LV diastolic dysfunction grade. Parameters of arterial stiffness and wave reflection are associated with echocardiographic indices of LV diastolic function in asymptomatic patients with DM. Therapies that prevent progression of arterial stiffness and reduce late-systolic pressure overload may help to reduce the prevalence of LV diastolic dysfunction in this population.     

Astroglial Responses to Amyloid-Beta Progression in a Mouse Model of Alzheimer’s Disease

Purpose

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by amyloid-beta (Aβ) deposition, hyperphosphorylation of tau, and neuroinflammation. Astrocytes, the most abundant glial cell type in the nervous system, respond to neurodegenerative disorders through astrogliosis, i.e., converting to a reactive inflammatory state. The aim of this study was to investigate how in vivo quantification of astrogliosis using positron emission tomography (PET) radioligand deuterium-l-[¹¹C]deprenyl ([¹¹C]DED), binding to enzyme monoamine oxidase-B (MAO-B) which is overexpressed in reactive astrocytes during AD, corresponds to expression of glial fibrillary acidic protein (GFAP) and vimentin, i.e., two well-established markers of astrogliosis, during Aβ pathology progression.

Procedures

APP_ArcSwe mice (n = 37) and wild-type (WT) control mice (n = 23), 2–16-month old, were used to investigate biomarkers of astrogliosis. The radioligand, [¹¹C]DED, was used as an in vivo marker while GFAP, vimentin, and MAO-B were used to investigate astrogliosis and macrophage-associated lectin (Mac-2) to investigate microglia/macrophage activation by immunohistochemistry of the mouse brain. Aβ and GFAP levels were also measured with ELISA in brain homogenates.

Results

The intrabrain levels of aggregated Aβ and reactive astrocytes were found to be elevated in APP_ArcSwe compared with WT mice. GFAP and vimentin expression increased with age, i.e., with Aβ pathology, in the APP_ArcSwe mice. This was not the case for in vivo marker [¹¹C]DED that showed elevated binding of the same magnitude in APP_ArcSwe mice compared with WT mice at both 8 and 16 months. Further, immunohistochemistry indicated that there was limited co-expression of MAO-B and GFAP.

Conclusions

MAO-B levels are increased early in Aβ pathology progression, while GFAP and vimentin appear to increase later, most likely as a consequence of abundant Aβ plaque formation. Thus, [¹¹C]DED is a useful PET radioligand for the detection of changes in MAO-B at an early stage of AD progression but does not measure the total extent of astrogliosis at advanced stages of Aβ pathology.

     

Comparison between Quantitative Stiffness Measurements and Ultrasonographic Findings of Fresh Carotid Plaques

Using a stiffness meter, we quantitatively measured the stiffness of fresh plaques that had been excised by carotid endarterectomy. The objective of this study was to clarify the correlation between plaque stiffness and pre-operative carotid ultrasonographic findings, and predict the stiffness of plaques before surgery by comparison with the stiffness of common items. The study population comprised 44 patients (44 lesions) who had undergone carotid endarterectomy at our institution between December 2009 and October 2014. The stiffness of excised fresh plaques was measured using a stiffness meter and compared with the pre-operative echographic findings for the plaques and the stiffness of selected foods and common items. The mean stiffness value for all plaques was 4.52 ± 3.30 MPa (mean ± standard deviation). The plaques exhibiting calcification were significantly harder (p = 0.001). On classification of lesions on the basis of echographic findings, plaque hardness was in the order low-echoic (15 lesions) < iso-echoic (20 lesions) < high-echoic (9 lesions) (p = 0.02). The stiffness of the low-echoic group was equivalent to that of tofu or sliced cheese, whereas the plaques in the iso- and high-echoic groups exhibited stiffness similar to that of ham and a plastic eraser, respectively. A significant correlation was observed between the quantitative stiffness values of carotid plaques and their brightness on carotid ultrasonography. Using these data, operators might be able to predict plaque stiffness from pre-operative echographic findings. In addition, it might be useful for operators to compare such quantitative stiffness measurements with stiffness data for foods and common items to gain an understanding of the state of the target plaque before treatment.     

Echo-Tracking Technology Assessment of Carotid Artery Stiffness in Patients with Coronary Slow Flow

Coronary slow flow (CSF) in coronary angiography (CAG) is a well-recognized clinical entity. Previous studies have suggested that microvascular abnormalities and endothelial dysfunction are responsible for CSF. Accordingly, we hypothesized that the CSF phenomenon is a form of atherosclerosis including both small vessels and epicardial coronary arteries. The echo-tracking (ET) technique is a non-invasive detection method for early prediction of arterial atherosclerosis. Therefore, we investigated carotid elasticity with the ET technique in patients with CSF. Fifty patients with CSF and 50 patients with normal coronary artery blood flow, as determined by CAG, with a similar distribution of risk factors were recruited. The stiffness parameter (β), pressure–strain elastic modulus (E_p), arterial compliance (AC), augmentation index (AIx) and local pulse-wave velocity (PWV) were determined at the level of the bilateral common carotid artery (CCA) with using the ET technique. Levels of serum high-sensitivity C-reactive protein (hs-HSCRP) were determined for the two groups. β, E_p and PWV were significantly higher in the CSF group than in the control group (β: 11.4 ± 3.76 vs. 9.22 ± 3.28, p < 0.01; E_p: 153.44 ± 47.85 vs. 126.40 ± 43.32, p < 0.01; PWV: 7.26 ± 1.10 vs. 6.55 ± 1.02, p < 0.01), but AC was lower in the CSF group than in the control group (0.62 ± 0.20 vs. 0.74 ± 0.24, p < 0.01). The elasticity parameters of the bilateral common carotid artery did not significantly differ. The level of hs-HSCRP was correlated positively with β (r = 0.306, p = 0.015), E_p (r = 0.358, p = 0.005) and PWV (r = 0.306, p = 0.015), but negatively with AC (r = −0.236, p = 0.049). In conclusion, the ET technique is a simple practical method for evaluating carotid artery elasticity, and there is a significant correlation between carotid artery stiffness and level of hs-HSCRP in patients with CSF.     

Serial assessment of arterial structure and function in patients with coarctation of the aorta undergoing stenting

Stenting for CoA has become an acceptable treatment modality in the last 20 years. However little is known about arterial changes after this procedure. To assess arterial structure and function including peripheral reactivity and stiffness and intima-media thickness (IMT) pre and post stenting for coarctation of the aorta (CoA). Twenty-one patients [median age: 15 years (8–39)] were studied at baseline, 1 day, 6 months and 1 year after stenting. Twenty-one healthy subjects (1:1 matched) were used as controls. Left ventricular (LV) mass, ejection fraction, flow-mediated dilation (FMD) and nitrate-mediated dilation (NMD) of left brachial artery, common carotid (CC) and right subclavian artery (RSCA) IMT and pulse wave velocity (PWV) were assessed by echocardiography and vascular ultrasound. CoA patients had higher LV indexed mass (p < 0.0001), impaired FMD (p < 0.0001) and NMD (p < 0.0001), increased PWV (p < 0.0001), carotid and RSCA IMT (both p < 0.0001). All procedures were successful and resulted in significant gradient reduction (p < 0.001). One year after stenting there was improvement in LV function (p = 0.034) and although there was significant reduction of LV mass (103.29 ± 24.77 vs. 74.39 ± 22.07 g/m², p < 0.0001) values did not normalize. There was no significant change in FMD, NMD, PWV and CC or RSCA IMT. In patients with CoA, arterial reactivity is impaired and LV mass, arterial stiffness and thickness are increased. Although stenting is successful to relieve the obstruction resulting in better LV function and mass reduction, arterial structure and function remains abnormal after 1 year of follow-up.     

A 18F-Labeled BF-227 Derivative as a Potential Radioligand for Imaging Dense Amyloid Plaques by Positron Emission Tomography

Purpose

The aims of this study were to evaluate the binding and pharmacokinetics of novel ¹⁸F-labeled ethenyl-benzoxazole derivatives (i.e., [¹⁸F] fluorinated amyloid imaging compound of Tohoku university ([¹⁸F]FACT)) as amyloid positron emission tomography (PET) tracers and to assess [¹⁸F]FACT efficacy in imaging of Alzheimer’s disease (AD).

Procedures

Binding assay was conducted using synthetic amyloid-β (Aβ) fibrils, fluorescence microscopy, and autoradiogram in three postmortem AD brains. Pharmacokinetics of [¹⁸F]FACT was assessed using 12 Crj:CD-1 (ICR) mice. In vivo binding ability with brain amyloid was investigated using amyloid precursor protein (APP) transgenic mouse. Clinical PET scanning using [¹⁸F]FACT was performed in ten healthy controls and ten mild cognitive impairment and ten AD patients.

Results

[¹⁸F]FACT showed high binding affinity for synthetic Aβ fibrils, preferential binding to dense cored plaques in brain sections, and excellent brain uptake and rapid clearance in mice. Injection in APP mice resulted in specific in vivo labeling of amyloid deposits in the brain. PET scans of AD patients showed significantly higher [¹⁸F]FACT uptake in the neocortex compared to controls (P?<?0.05, Kruskal–Wallis test).

Conclusion

[¹⁸F]FACT is a promising agent for imaging dense Aβ plaques in AD.     

Cerebral amyloid-β proteostasis is regulated by the membrane transport protein ABCC1 in mice

In Alzheimer disease (AD), the intracerebral accumulation of amyloid-β (Aβ) peptides is a critical yet poorly understood process. Aβ clearance via the blood-brain barrier is reduced by approximately 30% in AD patients, but the underlying mechanisms remain elusive. ABC transporters have been implicated in the regulation of Aβ levels in the brain. Using a mouse model of AD in which the animals were further genetically modified to lack specific ABC transporters, here we have shown that the transporter ABCC1 has an important role in cerebral Aβ clearance and accumulation. Deficiency of ABCC1 substantially increased cerebral Aβ levels without altering the expression of most enzymes that would favor the production of Aβ from the Aβ precursor protein. In contrast, activation of ABCC1 using thiethylperazine (a drug approved by the FDA to relieve nausea and vomiting) markedly reduced Aβ load in a mouse model of AD expressing ABCC1 but not in such mice lacking ABCC1. Thus, by altering the temporal aggregation profile of Aβ, pharmacological activation of ABC transporters could impede the neurodegenerative cascade that culminates in the dementia of AD.     

A Fully-Automatic Method to Segment the Carotid Artery Layers in Ultrasound Imaging: Application to Quantify the Compression-Decompression Pattern of the Intima-Media Complex During the Cardiac Cycle

The aim of this study was to introduce and evaluate a contour segmentation method to extract the interfaces of the intima–media complex in carotid B-mode ultrasound images. The method was applied to assess the temporal variation of intima–media thickness during the cardiac cycle. The main methodological contribution of the proposed approach is the introduction of an augmented dimension to process 2-D images in a 3-D space. The third dimension, which is added to the two spatial dimensions of the image, corresponds to the tentative local thickness of the intima–media complex. The method is based on a dynamic programming scheme that runs in a 3-D space generated with a shape-adapted filter bank. The optimal solution corresponds to a single medial axis representation that fully describes the two anatomical interfaces of the arterial wall. The method is fully automatic and does not require any input from the user. The method was trained on 60 subjects and validated on 184 other subjects from six different cohorts and four different medical centers. The arterial wall was successfully segmented in all analyzed images (average pixel size = 57 ± 20 μm), with average segmentation errors of 47 ± 70 μm for the lumen–intima interface, 55 ± 68 μm for the media–adventitia interface and 66 ± 90 μm for the intima–media thickness. The amplitude of the temporal variations in IMT during the cardiac cycle was significantly higher in the diseased population than in healthy volunteers (106 ± 48 vs. 86 ± 34 μm, p = 0.001). The introduced framework is a promising approach to investigate an emerging functional parameter of the arterial wall by assessing the cyclic compression–decompression pattern of the tissues.     

Quantification of aortic stiffness in stroke patients using 4D flow MRI in comparison with transesophageal echocardiography

To quantify stiffness of the descending aorta (DAo) in stroke patients using 4D flow MRI and compare results with transesophageal echocardiography (TEE). 48 acute stroke patients undergoing 4D flow MRI and TEE were included. Intima-media-thickness (IMT) was measured in the DAo and the aorta was scrutinized for atherosclerotic plaques using TEE. Stiffness of the DAo was determined by (a) 4D flow MRI at 3 T by calculating pulse wave velocity (PWV) and by (b) TEE calculating arterial strain, stiffness index, and distensibility coefficient. Mean IMT was 1.43?±?1.75. 7 (14.6%) subjects had no sign of atherosclerosis, 10 (20.8%) had IMT-thickening or plaques?<?4 mm, and 31 (66.7%) had at least one large and/or complex plaque in the aorta. Increased IMT significantly correlated (p?<?0.001) with increased DAo stiffness in MRI (PWV r?=?0.66) and in TEE (strain r?=?0.57, stiffness index r?=?0.64, distensibility coefficient r?=?0.57). Patients with at least IMT-thickening had significantly higher stiffness values compared to patients without atherosclerosis. However, no difference was observed between patients with plaques?<?4 mm and patients with plaques?≥?4 mm. PWV and TEE parameters of stiffness correlated significantly [strain (r?=???0.36; p?=?0.011), stiffness index (r?=?0.51; p?=?0.002), and distensibility coefficient (r?=???0.59; p?<?0.001)]. 4D flow MRI and TEE-based parameters of aortic stiffness were associated with markers of atherosclerosis such as IMT-thickness and presence of plaques. We believe that 4D flow MRI is a promising tool for future studies of aortic atherosclerosis, due to its longer coverage of the aorta and non-invasiveness.     

Evaluation of Post-Stroke Spastic Muscle Stiffness Using Shear Wave Ultrasound Elastography

Current clinical evaluations of post-stroke upper limb spasticity are subjective and qualitative. We proposed a quantitative measurement of post-stroke spastic muscle stiffness by using shear-wave ultrasound elastography and tested its reliability. Acoustic radiation force impulse with shear wave velocity (SWV) detection was used to evaluate stiffness of the biceps brachii muscles at 90° and 0° elbow flexion. In 21 control subjects, SWV did not significantly differ between dominant and non-dominant sides at either flexion angle (0°: p = 0.311, 90°: p = 0.436). In 31 patients who had recent stroke, SWV was significantly greater on the paretic side than on the non-paretic side at both 90° (2.23 ± 0.15 m/s vs. 1.88 ± 0.08 m/s, p = 0.036) and 0° (3.28 ± 0.11 m/s vs. 2.93 ± 0.06 m/s, p = 0.002). The physical appearance of arms and forearms of our patients and controls prevented blinding of the rater to paretic or non-paretic side. At 90°, SWV on the paretic side correlated positively with modified Ashworth scale and modified Tardieu scale (spasticity severity) and negatively with Stroke Rehabilitation Assessment of Movement score (motor function impairment). The intra-class correlation coefficients of intra-rater and inter-rater reliability for SWV measurements were classified as excellent. In conclusion, high SWV was associated with high spasticity and poor function of the post-stroke upper limb, suggesting possible use as a reliable quantitative measure for disease progression and treatment follow-up.     

Aortic stiffness and carotid intima‐media thickness: two independent markers of subclinical vascular damage in young adults?

BACKGROUND: Previous reports have shown that carotid intima-media thickness (CIMT) and arterial stiffness are strong predictors of subsequent cardiovascular disease (CVD) morbidity and mortality, and are well related to an unfavourable cardiovascular risk profile in middle-aged and older subjects. These similarities suggest that arterial stiffness may play a role in the development of atherosclerosis or vice versa. However, studies show conflicting results and are limited to elderly subjects. To study this issue further, we evaluated the relation of arterial stiffness to subclinical atherosclerosis in 524 healthy young adults, aged 27-30 years. METHODS AND RESULTS: Aortic stiffness was assessed using pulse wave velocity (PWV) and CIMT was used as measure of subclinical atherosclerosis. The positive crude correlation between for mean arterial pressure adjusted PWV and CIMT (Pearson's correlation coefficient: 0.11; P=0.016) attenuated after adjustment for common determinants of both measurements like gender and age (partial correlation coefficient: 0.03; P=0.512). Furthermore, multivariate linear regression models showed that male gender, age and blood pressure were independent determinants of both CIMT and PWV while body mass index and LDL-cholesterol were independent determinants of CIMT only. CONCLUSIONS: These observations suggest that in healthy young adults arterial stiffness and CIMT reflect two separate entities of vascular damage.     

Measurement of regional pulse wave velocity using very high frame rate ultrasound

Purpose

Pulse wave velocity (PWV) is the propagation velocity of the pressure wave along the artery due to the heartbeat. The PWV becomes faster with progression of arteriosclerosis and, thus, can be used as a diagnostic index of arteriosclerosis. Measurement of PWV is known as a noninvasive approach for diagnosis of arteriosclerosis and is widely used in clinical situations. In the traditional PWV method, the average PWV is calculated between two points, the carotid and femoral arteries, at an interval of several tens of centimeters. However, PWV depends on part of the arterial tree, i.e., PWVs in the distal arteries are faster than those in the proximal arteries. Therefore, measurement of regional PWV is preferable.

Methods

To evaluate regional PWV in the present study, the minute vibration velocity of the human carotid arterial wall was measured at intervals of 0.2 mm at 72 points in the arterial longitudinal direction by the phased-tracking method at a high temporal resolution of 3472 Hz, and PWV was estimated by applying the Hilbert transform to those waveforms.

Results

In the present study, carotid arteries of three healthy subjects were measured in vivo. The PWVs in short segments of 14.4 mm in the arterial longitudinal direction were estimated to be 5.6, 6.4, and 6.7 m/s, which were in good agreement with those reported in the literature. Furthermore, for one of the subjects, a component was clearly found propagating from the periphery to the direction of the heart, i.e., a well known component reflected by the peripheral arteries. By using the proposed method, the propagation speed of the reflection component was also separately estimated to be ?8.4 m/s. The higher magnitude of PWV for the reflection component was considered to be the difference in blood pressure at the arrivals of the forward and reflection components.

Conclusion

Such a method would be useful for more sensitive evaluation of the change in elasticity due to progression of arteriosclerosis by measuring the regional PWV in a specific artery of interest (not the average PWV including other arteries).     

Thalidomide influences atherogenesis in aortas of ApoE−/−/LDLR−/− double knockout mice: a nano-CT study

Plaque progression in atherosclerosis is closely connected to angiogenesis due to vasa vasorum (VV) growth. Objective of this study was to determine the unknown long-term effect of thalidomide on adventitial VV neovascularization and plaque progression using nano-focussed computed tomography (nano-CT). Proliferation and migration assays in human coronary artery endothelial cells (HCAEC) measured number of viable cells after incubation with thalidomide. Male ApoE^?/?/LDLR^?/? (AL) mice (n = 5) received a thalidomide containing western diet (WD) over 29 weeks. Another five male AL mice (WD without thalidomide) served as control group. Descending aortas were scanned with nano-CT at (1.5 μm)³ isotropic voxel size. Number and area of adventitial VV as well as plaque cross sectional area were measured. Results were complemented by histology. Thalidomide inhibited proliferation and migration of HCAEC dose-dependently. VV neovascularization decreased in number per cross section (7.66 ± 0.301 vs. 8.62 ± 0.164, p < 0.001) and in cross sectional area (0.0183 ± 0.0011 vs. 0.0238 ± 0.0008 mm², p < 0.001). Cross sectional area of plaque decreased significantly when treated with thalidomide (0.57 ± 0.0187 vs. 0.803 ± 0.0148 mm², p < 0.001). Nano-CT imaging revealed a reduced plaque growth and VV neovascularization after long-term application of thalidomide. Therefore, nano-CT can be considered as a new method to detect therapeutic effects in experimental models of atherosclerosis.     

Carotid Artery Stiffness Mechanisms in Hypertension and Their Association with Echolucency and Texture Features: The Multi-ethnic Study of Atherosclerosis (MESA)

Arterial stiffness, echolucency and texture features are altered with hypertension and associated with increased cardiovascular disease risk. The relationship between these markers and structural and load-dependent artery wall changes in hypertension are poorly understood. The Multi-ethnic Study of Atherosclerosis (MESA) is a longitudinal study of 6814 adults from six communities across the United States designed to study subclinical cardiovascular disease. From B-mode imaging of the right common carotid artery at the baseline MESA examination, we calculated carotid artery Young's elastic modulus (YEM, n = 5894) and carotid artery gray-scale texture features (n = 1403). The standard YEM calculation represented total arterial stiffness. Structural stiffness was calculated by adjusting YEM to a standard blood pressure of 120/80 mm Hg with participant-specific models. Load-dependent stiffness was the difference between total and structural stiffness. We found that load-dependent YEM was elevated in hypertensive individuals compared with normotensive individuals (35.7 ± 105.5 vs. –62.0 ± 112.4 kPa, p < 0.001) but that structural YEM was similar (425.3 ± 274.8 vs. 428.4 ± 293.0 kPa, p = 0.60). Gray-scale measures of heterogeneity in carotid artery wall texture (gray-level difference statistic contrast) had small but statistically signification correlations with carotid artery stiffness mechanisms. This association was positive for structural YEM (0.107, p < 0.001), while for load-dependent YEM, the association was negative (–0.064, p = 0.02). In conclusion, increased arterial stiffness in hypertension was owing solely to the non-linear mechanics of having higher blood pressure, not structural changes in the artery wall, and high load-dependent stiffness was associated with a more homogenous carotid artery wall texture. This is potentially related to arterial remodeling associated with subclinical atherosclerosis and future cardiovascular disease development. These results also indicate that gray-scale texture features from ultrasound imaging had a small but statistically significant association with load-dependent arterial stiffness and that gray-scale texture features may be partially load dependent.     

An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer's disease- associated Aβ oligomers

Defective brain insulin signaling has been suggested to contribute to the cognitive deficits in patients with Alzheimer's disease (AD). Although a connection between AD and diabetes has been suggested, a major unknown is the mechanism(s) by which insulin resistance in the brain arises in individuals with AD. Here, we show that serine phosphorylation of IRS-1 (IRS-1pSer) is common to both diseases. Brain tissue from humans with AD had elevated levels of IRS-1pSer and activated JNK, analogous to what occurs in peripheral tissue in patients with diabetes. We found that amyloid-β peptide (Aβ) oligomers, synaptotoxins that accumulate in the brains of AD patients, activated the JNK/TNF-α pathway, induced IRS-1 phosphorylation at multiple serine residues, and inhibited physiological IRS-1pTyr in mature cultured hippocampal neurons. Impaired IRS-1 signaling was also present in the hippocampi of Tg mice with a brain condition that models AD. Importantly, intracerebroventricular injection of Aβ oligomers triggered hippocampal IRS-1pSer and JNK activation in cynomolgus monkeys. The oligomer-induced neuronal pathologies observed in vitro, including impaired axonal transport, were prevented by exposure to exendin-4 (exenatide), an anti-diabetes agent. In Tg mice, exendin-4 decreased levels of hippocampal IRS-1pSer and activated JNK and improved behavioral measures of cognition. By establishing molecular links between the dysregulated insulin signaling in AD and diabetes, our results open avenues for the investigation of new therapeutics in AD.