Image-based gradient non-linearity characterization to determine higher-order spherical harmonic coefficients for improved spatial position accuracy in magnetic resonance imaging

Publication date: May 2017
Source:Magnetic Resonance Imaging, Volume 38
Author(s): Paul T. Weavers, Shengzhen Tao, Joshua D. Trzasko, Yunhong Shu, Erik J. Tryggestad, Jeffrey L. Gunter, Kiaran P. McGee, Daniel V. Litwiller, Ken-Pin Hwang, Matt A. Bernstein
PurposeSpatial position accuracy in magnetic resonance imaging (MRI) is an important concern for a variety of applications, including radiation therapy planning, surgical planning, and longitudinal studies of morphologic changes to study neurodegenerative diseases. Spatial accuracy is strongly influenced by gradient linearity. This work presents a method for characterizing the gradient non-linearity fields on a per-system basis, and using this information to provide improved and higher-order (9th vs. 5th) spherical harmonic coefficients for better spatial accuracy in MRI.MethodsA large fiducial phantom containing 5229 water-filled spheres in a grid pattern is scanned with the MR system, and the positions all the fiducials are measured and compared to the corresponding ground truth fiducial positions as reported from a computed tomography (CT) scan of the object. Systematic errors from off-resonance (i.e., B0) effects are minimized with the use of increased receiver bandwidth (±125kHz) and two acquisitions with reversed readout gradient polarity. The spherical harmonic coefficients are estimated using an iterative process, and can be subsequently used to correct for gradient non-linearity. Test-retest stability was assessed with five repeated measurements on a single scanner, and cross-scanner variation on four different, identically-configured 3T wide-bore systems.ResultsA decrease in the root-mean-square error (RMSE) over a 50cm diameter spherical volume from 1.80mm to 0.77mm is reported here in the case of replacing the vendor's standard 5th order spherical harmonic coefficients with custom fitted 9th order coefficients, and from 1.5mm to 1mm by extending custom fitted 5th order correction to the 9th order. Minimum RMSE varied between scanners, but was stable with repeated measurements in the same scanner.ConclusionsThe results suggest that the proposed methods may be used on a per-system basis to more accurately calibrate MR gradient non-linearity coefficients when compared to vendor standard corrections.



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A simple analytic method for estimating T2 in the knee from DESS

Publication date: May 2017
Source:Magnetic Resonance Imaging, Volume 38
Author(s): B Sveinsson, AS Chaudhari, GE Gold, BA Hargreaves
PurposeTo introduce a simple analytical formula for estimating T2 from a single Double-Echo in Steady-State (DESS) scan.MethodsExtended Phase Graph (EPG) modeling was used to develop a straightforward linear approximation of the relationship between the two DESS signals, enabling accurate T2 estimation from one DESS scan. Simulations were performed to demonstrate cancellation of different echo pathways to validate this simple model. The resulting analytic formula was compared to previous methods for T2 estimation using DESS and fast spin-echo scans in agar phantoms and knee cartilage in three volunteers and three patients. The DESS approach allows 3D (256×256×44) T2-mapping with fat suppression in scan times of 3–4min.ResultsThe simulations demonstrated that the model approximates the true signal very well. If the T1 is within 20% of the assumed T1, the T2 estimation error was shown to be less than 5% for typical scans. The inherent residual error in the model was demonstrated to be small both due to signal decay and opposing signal contributions. The estimated T2 from the linear relationship agrees well with reference scans, both for the phantoms and in vivo. The method resulted in less underestimation of T2 than previous single-scan approaches, with processing times 60 times faster than using a numerical fit.ConclusionA simplified relationship between the two DESS signals allows for rapid 3D T2 quantification with DESS that is accurate, yet also simple. The simplicity of the method allows for immediate T2 estimation in cartilage during the MRI examination.



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Semi-quantitative analysis of salivary gland scintigraphy in Sjögren’s syndrome diagnosis: a first-line tool

Abstract

Objective

The aim of this study was the assessment of semi-quantified salivary gland dynamic scintigraphy (SGdS) parameters independently and in an integrated way in order to predict primary Sjögren's syndrome (pSS).

Materials and methods

Forty-six consecutive patients (41 females; age 61 ± 11 years) with sicca syndrome were studied by SGdS after injection of 200 MBq of pertechnetate. In sixteen patients, pSS was diagnosed, according to American-European Consensus Group criteria (AECGc).

Semi-quantitative parameters (uptake (UP) and excretion fraction (EF)) were obtained for each gland. ROC curves were used to determine the best cut-off value. The area under the curve (AUC) was used to estimate the accuracy of each semi-quantitative analysis.

To assess the correlation between scintigraphic results and disease severity, semi-quantitative parameters were plotted versus Sjögren's syndrome disease activity index (ESSDAI). A nomogram was built to perform an integrated evaluation of all the scintigraphic semi-quantitative data.

Results

Both UP and EF of salivary glands were significantly lower in pSS patients compared to those in non-pSS (p < 0.001). ROC curve showed significantly large AUC for both the parameters (p < 0.05).

Parotid UP and submandibular EF, assessed by univariated and multivariate logistic regression, showed a significant and independent correlation with pSS diagnosis (p value <0.05). No correlation was found between SGdS semi-quantitative parameters and ESSDAI. The proposed nomogram accuracy was 87%.

Conclusion

SGdS is an accurate and reproducible tool for the diagnosis of pSS. ESSDAI was not shown to be correlated with SGdS data.

Clinical relevance

SGdS should be the first-line imaging technique in patients with suspected pSS.

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Head-to-head comparison between 18 F-FDOPA PET/CT and MR/CT angiography in clinically recurrent head and neck paragangliomas

Abstract

Purpose

Head and neck paragangliomas (HNPGLs) can relapse after primary treatment. Optimal imaging protocols have not yet been established for posttreatment evaluation. The aim of the present study was to assess the diagnostic value of ¹⁸F-FDOPA PET/CT and MR/CT angiography (MRA/CTA) in HNPGL patients with clinical relapse during their follow-up.

Methods

Sixteen consecutive patients presenting with local pain, tinnitus, dysphagia, hoarse voice, cranial nerve involvement, deafness, or retrotympanic mass appearing during follow-up after the initial treatment of HNPGLs were retrospectively evaluated. Patients underwent both ¹⁸F-FDOPA PET/CT and MRA (15 patents) or CTA (1 patent). Both methods were first assessed under blinded conditions and afterwards correlated. Head and neck imaging abnormalities without histological confirmation were considered true-positive results based on a consensus between radiologists and nuclear physicians and on further ¹⁸F-FDOPA PET/CT and/or MRA.

Results

¹⁸F-FDOPA PET/CT and MRA/CTA were concordant in 14 patients and in disagreement in 2 patients. ¹⁸F-FDOPA PET/CT and MRA/CTA identified, respectively, 12 and 10 presumed recurrent HNPGLs in 12 patients. The two lesions diagnosed by PET/CT only were confirmed during follow-up by otoscopic examination and MRA performed 29 and 17 months later. ¹⁸F-FDOPA PET/CT images were only slightly influenced by the posttreatment sequelae, showing a better interobserver reproducibility than MRA/CTA. Finally, in 2 of the 16 studied patients, ¹⁸F-FDOPA PET/CT detected two additional synchronous primary HNPGLs.

Conclusion

¹⁸F-FDOPA PET/CT is highly sensitive in posttreatment evaluation of patients with HNPGLs, and also offers better interobserver reproducibility than MRA/CTA and whole-body examination. We therefore suggest that ¹⁸F-FDOPA PET/CT is performed as the first diagnostic imaging modality in symptomatic patients with suspicion of HNPGL relapse after primary treatment when ⁶⁸Ga-labeled somatostatin analogues are not available.

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Outcomes of an inpatient refeeding protocol in youth with anorexia nervosa: Rady Children’s Hospital San Diego/University of California, San Diego

Abstract

Background

Current guidelines for nutritional rehabilitation in hospitalized restrictive eating disorder patients recommend a cautious approach to refeeding. Several studies suggest that higher calorie diets may be safe and effective, but have traditionally excluded severely malnourished patients. The goal of this study was to evaluate the safety of a higher calorie nutritional rehabilitation protocol (NRP) in a broad sample of inpatients with restrictive eating disorders, including those who were severely malnourished.

Methods

A retrospective chart review was conducted among eating disorder inpatients between January 2015 and March 2016. Patients were started on a lower calorie diet (≤1500 kcals/day) or higher calorie diet (≥1500 kcals/day). Calorie prescription on admission was based on physician clinical judgement. The sample included patients aged 8–20 years with any DSM-5 restrictive eating disorder. Those who were severely malnourished (<75% expected body weight [EBW]) or required tube feeding during admission were included. Multivariable regression models were used to determine whether level of nutritional rehabilitation was associated with hypophosphatemia, hypomagnesemia, or hypokalemia.

Results

The sample included 87 patients; mean age was 14.4 years (S.D. 32.7); 29% were <75% EBW. The majority (75.8%) was started on higher calorie diets (mean 1781 kcal/day). Controlling for rate of calorie change, initial %EBW, age, race/ethnicity, insurance, diagnosis, and NG/NJ tube placement, higher calorie diets were not associated with hypophosphatemia, hypomagnesemia, or hypokalemia on admission or within the first 72 h. Increased risk of hypophosphatemia on admission was associated with lower baseline %EBW.

Conclusion

A higher calorie NRP was tolerated in this broad population of inpatients with restrictive eating disorders. Lower %EBW on admission was a more important predictor of hypophosphatemia than initial calorie level. Larger studies are required to demonstrate the safety of higher calorie diets in severely malnourished patients.

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Happy New Year from the ATA

The post Happy New Year from the ATA appeared first on American Thyroid Association.

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Editorial Board

Publication date: January 2017
Source:Dental Materials, Volume 33, Issue 1





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Surface modified zeolite-based granulates for the sustained release of diclofenac sodium

Publication date: 1 March 2017
Source:European Journal of Pharmaceutical Sciences, Volume 99
Author(s): Carla Serri, Bruno de Gennaro, Vincenzo Quagliariello, Rosario Vincenzo Iaffaioli, Giuseppe De Rosa, Lilia Catalanotti, Marco Biondi, Laura Mayol
In this study, a granulate for the oral controlled delivery of diclofenac sodium (DS), an anionic sparingly soluble nonsteroidal anti-inflammatory drug, has been realized by wet granulation, using a surface modified natural zeolite (SMNZ) as an excipient. The surface modification of the zeolite has been achieved by means of a cationic surfactant, so as to allow the loading of DS through ionic interaction and bestow a control over the drug release mechanism. The granules possessed a satisfactory dosage uniformity, a flowability suitable for an oral dosage form manufacturing, along with a sustained drug release up to 9h, driven by both ion exchange and transport kinetics. Furthermore, the obtained granulate did not elicit a significant cytotoxicity and could also induce a prolonged anti-inflammatory effect on RAW264.7 cells. Taking also into account that natural zeolites are generally abundant and economic, SMNZ can be considered as an attracting alternative excipient for the production of granules with sustained release features.

Graphical abstract

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Towards prostate cancer gene therapy: Development of a chlorotoxin-targeted nanovector for toxic (melittin) gene delivery

Publication date: 1 March 2017
Source:European Journal of Pharmaceutical Sciences, Volume 99
Author(s): Zahra Tarokh, Hossein Naderi-Manesh, Mahboobeh Nazari
Prostate cancer is the second leading cause of death due to cancer in men. Owing to shortcomings in the current treatments, other therapies are being considered. Toxic gene delivery is one of the most effective methods for cancer therapy. Cationic polymers are able to form stable nanoparticles via interaction with nucleic acids electrostatically. Branched polyethylenimine that contains amine groups has notable buffering capacity and the ability to escape from endosome through the proton sponge effect. However, the cytotoxicity of this polymer is high, and modification is one of the applicable strategies to overcome this problem. In this study, PEI was targeted with chlorotoxin (CTX) via N-succinimidyl 3-(2-pyridyldithio) propionate (SPDP) cross-linker. CTX can bind specifically to matrix metalloproteinase-2 that is overexpressed in certain cancers. Melittin as the major component of bee venom has been reported to have anti-cancer activity. This was thus selected to deliver to PC3 cell line. Flow cytometry analysis revealed that transfection efficiency of targeted nanoparticles is significantly higher compared to non-targeted nanoparticles. Targeted nanoparticles carrying the melittin gene also decreased cell viability of PC3 cells significantly while no toxic effects were observed on NIH3T3 cell line. Therefore, CTX-targeted nanoparticles carrying the melittin gene could serve as an appropriate gene delivery system for prostate and other MMP-2 positive cancer cells.

Graphical abstract

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Drug-drug cocrystals of antituberculous 4-aminosalicylic acid: Screening, crystal structures, thermochemical and solubility studies

Publication date: 1 March 2017
Source:European Journal of Pharmaceutical Sciences, Volume 99
Author(s): Ksenia V. Drozd, Alex N. Manin, Andrei V. Churakov, German L. Perlovich
Experimental multistage cocrystal screening of the antituberculous drug 4-aminosalicylic acid (PASA) has been conducted with a number of coformers (pyrazinamide (PYR), nicotinamide (NAM), isonicotinamide (iNAM), isoniazid (INH), caffeine (CAF) and theophylline (TPH)). The crystal structures of 4-aminosalicylic acid cocrystals with isonicotinamide ([PASA+iNAM] (2:1)) and methanol solvate with caffeine ([PASA+CAF+MeOH] (1:1:1)) have been determined by single X-ray diffraction experiments. For the first time for PASA cocrystals it has been found that the structural unit of the [PASA+iNAM] cocrystal (2:1) is formed by 2 types of heterosynthons: acid-pyridine and acid-amide. The desolvation study of the [PASA+CAF+MeOH] cocrystal solvate (1:1:1) has been conducted. The correlation models linking the melting points of the cocrystals with the melting points of the coformers used in this paper have been developed. The thermochemical and solubility properties for all the obtained cocrystals have been studied. Cocrystallization has been shown to lead not only to PASA solubility improving but also to its higher stability against the chemical decomposition.

Graphical abstract

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Upper Extremity Blood Pressure Difference in Patients Undergoing Carotid Revascularisation

Publication date: Available online 3 January 2017
Source:European Journal of Vascular and Endovascular Surgery
Author(s): A. Huibers, J. Hendrikse, M.M. Brown, S.A. Pegge, M. Arnold, F.L. Moll, L.J. Kapelle, G.J. de Borst
IntroductionBlood pressure (BP) regulation is important in patients with carotid artery atherosclerotic disease. Concomitant subclavian artery stenosis (SAS) might lead to an underestimation of the true systemic BP in the monitoring of these patients. This study aimed to assess the prevalence of the inter-arm BP difference in patients undergoing carotid intervention and its association with ipsilateral significant subclavian stenosis and clinical outcome.MethodsBilateral BP measurements and vascular imaging (CTA and MRA) of both subclavian arteries and the innominate artery were assessed in 182 symptomatic patients with carotid artery stenosis undergoing revascularisation in the International Carotid Stenting Study (ICSS). Data were separately analysed according to previously described cutoff values for systolic BP (SBP) differences of ≥10 and <15 mmHg, ≥15 and <20 mmHg, or ≥20 mmHg. Significant SAS was defined as a >50% diameter reduction.ResultsOf the 182 patients, 39 (21%) showed an inter-arm difference in SBP >15 mmHg. The mean inter-arm SBP difference associated with ipsilateral SAS was 14 mmHg. SAS was present in 21/182 (12%) patients. Only two patients (1%) had bilateral stenotic disease. An inter-arm SBP difference of ≥20 mmHg was associated with unilateral SAS (RR 11.8; 95% CI 3.2–43.1) with a sensitivity of 23% and a specificity of 98%. Patients were followed up for a median of 4.0 years (IQR 3.0–6.0; maximum 7.5). Risk of stroke or death during follow-up was 20.0% (95% CI 11.1–28.9) in patients with, and 15.1% (95% CI 12.3–17.9) in patients without SAS (p = .561). The hospital stay was longer in patients with significant SAS (5.0 days, SD 4.9 vs. 2.7 days, SD 4.3, p = .035).ConclusionThe present study is the first to affirm the clinical need for the measurement of inter-arm BP differences in patients undergoing carotid revascularisation, especially in the post-operative phase in the prevention of cerebral hyperperfusion.



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Highly efficient photocatalytic performances of SnO2-deposited ZnS nanorods based on interfacial charge transfer

Publication date: 15 May 2017
Source:Applied Catalysis B: Environmental, Volume 205
Author(s): Jaewon Lee, Yeonho Kim, Joon Ki Kim, Seongchan Kim, Dal-Hee Min, Du-Jeon Jang
SnO2/ZnS nanocomposites of SnO2 quantum dots (QDs)-deposited ZnS nanorods having highly enhanced photocatalytic activity and photostability have been fabricated via a facile two-step hydrazine-assisted hydrothermal process without involving any surface treatments. The photocatalytic activity of SnO2/ZnS nanocomposites with a Sn-to-Zn molar ratio (RSn/Zn) of 0.1 is 3 times higher than that of pristine ZnS nanorods and 17 times higher than that of commercial ZnS. The incorporation of SnO2 QDs increases the photocatalytic efficiency of ZnS nanorods due to the following reasons: photogenerated charge carriers are readily separated owing to type II band configuration and direct contact at interfaces without having any linker molecules; active surface sites are increased to adsorb more dye molecules; the light absorption range is extended to the visible region, generating more charge carriers on the surfaces of heterojunction structures. The decay time, as well as the intensity, of the band-edge emission of SnO2/ZnS nanocomposites at 325nm decreases progressively and rapidly with the increase of RSn/Zn, indicating that fast electron transfer takes place from photoexcited ZnS nanorods to SnO2 QDs. Thus, the higher photocatalytic degradation efficiencies of SnO2/ZnS nanocomposites are considered to result mainly from the increased separation rates of photogenerated charges. The photostability of SnO2/ZnS nanocomposites is also improved due to the protection and charge-separation effects of decorating SnO2 QDs. Our prepared SnO2/ZnS nanocomposites are suggested to have great potential for photodegradation nanocatalysts in the field of waste-water treatment.

Graphical abstract

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Cu2ZnSnS4 thin films obtained by sulfurization of evaporated Cu2SnS3 and ZnS layers: Influence of the ternary precursor features

Publication date: 1 April 2017
Source:Applied Surface Science, Volume 400
Author(s): V. Robles, C. Guillén, J.F. Trigo, J. Herrero
Cu2ZnSnS4 (CZTS) thin films have been grown by sulfurization of Cu2SnS3 (CTS) and ZnS layers evaporated on glass substrates. Four CTS precursor films have been tested, with two different atomic compositions (Cu/Sn=1.7 and Cu/Sn=2.1) and substrate temperatures (350 and 450°C), together with analogous ZnS layers deposited by maintaining the substrate at 200°C. The sulfurization of the CTS and ZnS stacked layers was performed at 500°C during 1h. The evolution of the crystalline structure, morphology, optical and electrical properties from each CTS precursor to the CZTS compound has been studied, especially the influence of the ternary precursor features on the quaternary film characteristics. The kesterite structure has been identified after sulfurization of the various samples, with main (112) orientation and mean crystallite sizes S112=40–56nm, being higher for the Cu-poor compositions. The CZTS average roughness has varied in a wide interval Ra=8–66nm, being directly related to the CTS precursor layer, which becomes rougher for a higher deposition temperature or Cu content. Besides, the band gap energy and the electrical resistivity of the CZTS films have changed in the ranges Eg=1.54–1.64eV and ρ=0.2–40Ωcm, both decreasing when the Cu content and/or the surface roughness increase.

Graphical abstract

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Vineland-II adaptive behavior profile of children with attention-deficit/hyperactivity disorder or specific learning disorders

Publication date: February 2017
Source:Research in Developmental Disabilities, Volume 61
Author(s): Giulia Balboni, Oriana Incognito, Carmen Belacchi, Sabrina Bonichini, Roberto Cubelli
BackgroundThe evaluation of adaptive behavior is informative in children with attention-deficit/hyperactivity disorder (ADHD) or specific learning disorders (SLD). However, the few investigations available have focused only on the gross level of domains of adaptive behavior.AimsTo investigate which item subsets of the Vineland-II can discriminate children with ADHD or SLD from peers with typical development.Methods and proceduresStudent's t-tests, ROC analysis, logistic regression, and linear discriminant function analysis were used to compare 24 children with ADHD, 61 elementary students with SLD, and controls matched on age, sex, school level attended, and both parents' education level.ResultsSeveral item subsets that address not only ADHD core symptoms, but also understanding in social context and development of interpersonal relationships, allowed discrimination of children with ADHD from controls. The combination of four item subsets (Listening and attending, Expressing complex ideas, Social communication, and Following instructions) classified children with ADHD with both sensitivity and specificity of 87.5%. Only Reading skills, Writing skills, and Time and dates discriminated children with SLD from controls.ConclusionsEvaluation of Vineland-II scores at the level of item content categories is a useful procedure for an efficient clinical description.



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Myocardial blood flow and left ventricular functional reserve in hypertrophic cardiomyopathy: a 13 NH 3 gated PET study

Abstract

Introduction

Ischemia in hypertrophic cardiomyopathy (HCM) is caused by coronary microvascular dysfunction (CMD), which is detected by measuring myocardial blood flow (MBF) with PET. Whether CMD may be associated with ischemic left ventricular (LV) dysfunction is unclear. We therefore assessed LV ejection fraction (EF) reserve in HCM patients undergoing dipyridamole (Dip) PET.

Methods

Resting and stress ¹³NH₃ dynamic as well as gated PET were performed in 34 HCM patients. Segmental MBF and transmural perfusion gradient (TPG = subendocardial / subepicardial MBF) were assessed. LVEF reserve was considered abnormal if Dip LVEF decreased more than 5 units as compared to rest.

Results

Eighteen patients had preserved (group A) and 16 abnormal LVEF reserve (group B; range −7 to −32). Group B patients had greater wall thickness than group A, but resting volumes, LVEF, resting and Dip MBF, and myocardial flow reserve were similar. Group B had slightly higher summed stress score and summed difference score in visual analysis than group A, and a significantly higher summed stress wall motion score. In group B, resting TPG was slightly lower (1.31 ± 0.29 vs. 1.37 ± 0.34, p <0.05), and further decreased after Dip, whilst in group A it increased (B = 1.20 ± 0.39, p < 0.0001 vs. rest and vs. A = 1.40 ± 0.43). The number of segments per patient with TPG <1 was higher than in group A (p < 0.001) and was a significant predictor of impaired LVEF reserve (OR 1.86, p < 0.02), together with wall thickness (OR 1.3, p < 0.02).

Conclusion

Abnormal LVEF response is common in HCM patients following Dip, and is related to abnormal TPG, suggesting that subendocardial ischemia might occur under Dip and cause transient LV dysfunction. Although in vivo this effect may be hindered by the adrenergic drive associated with effort, these findings may have relevance in understanding exercise limitation and heart failure symptoms in HCM.

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Executive Function Performance and Change in Aging is Predicted by Apolipoprotein E, Intensified by Catechol-O-methyltransferase and Brain-derived neurotrophic factor, and Moderated by Age and Lifestyle

Publication date: Available online 3 January 2017
Source:Neurobiology of Aging
Author(s): Shraddha Sapkota, Lars Bäckman, Roger A. Dixon
Recent studies have reported several genetic, health, and aging interaction effects in predicting cognitive performance and change. We used an accelerated longitudinal design to examine interactions among genetic, lifestyle, and aging for executive function (EF) in non-demented older adults (n=634; age range=53-95 years). The polymorphisms were Apolipoprotein E (APOE),Catechol-O-methyl transferase (COMT), and Brain-derived neurotrophic factor (BDNF). We tested (a) independent and additive effects of APOE, COMT, and BDNF and (b) APOE effect modification for COMT+ BDNF, on EF performance and 9-year change as separated by age and lifestyle activities. First, APOE ε4+ carriers had poorer EF performance and steeper 9-year decline. Second, APOE ε4+ carriers with (a) BDNF Met/Met genotype and (b) increasing allelic risk in the COMT+ BDNF risk panel had poorer EF performance; these effects were moderated by lifestyle activities (composite of everyday social, physical, cognitive activities). Examining APOE effect modification for COMT+ BDNF risk panel effects with other moderating factors may help identify complex neurobiological and genetic underpinnings of polygenic phenotypes such as EF in aging.



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Administrations of human adult ischemia-tolerant mesenchymal stem cells and factors reduce amyloid beta pathology in a mouse model of Alzheimer's disease

Publication date: March 2017
Source:Neurobiology of Aging, Volume 51
Author(s): Taoufiq Harach, Fabien Jammes, Charles Muller, Nicolas Duthilleul, Victoria Cheatham, Valentin Zufferey, David Cheatham, Yelizaveta A. Lukasheva, Theo Lasser, Tristan Bolmont
The impact of human adult ischemia-tolerant mesenchymal stem cells (hMSCs) and factors (stem cell factors) on cerebral amyloid beta (Aβ) pathology was investigated in a mouse model of Alzheimer's disease (AD). To this end, hMSCs were administered intravenously to APPPS1 transgenic mice that normally develop cerebral Aβ. Quantitative reverse transcriptase polymerase chain reaction biodistribution revealed that intravenously delivered hMSCs were readily detected in APPPS1 brains 1 hour following administration, and dropped to negligible levels after 1 week. Notably, intravenously injected hMSCs that migrated to the brain region were localized in the cerebrovasculature, but they also could be observed in the brain parenchyma particularly in the hippocampus, as revealed by immunohistochemistry. A single hMSC injection markedly reduced soluble cerebral Aβ levels in APPPS1 mice after 1 week, although increasing several Aβ-degrading enzymes and modulating a panel of cerebral cytokines, suggesting an amyloid-degrading and anti-inflammatory impact of hMSCs. Furthermore, 10 weeks of hMSC treatment significantly reduced cerebral Aβ plaques and neuroinflammation in APPPS1 mice, without increasing cerebral amyloid angiopathy or microhemorrhages. Notably, a repeated intranasal delivery of soluble factors secreted by hMSCs in culture, in the absence of intravenous hMSC injection, was also sufficient to diminish cerebral amyloidosis in the mice. In conclusion, this preclinical study strongly underlines that cerebral amyloidosis is amenable to therapeutic intervention based on peripheral applications of hMSC or hMSC factors, paving the way for a novel therapy for Aβ amyloidosis and associated pathologies observed in AD.



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Quercetin-3-O-glucuronide promotes the proliferation and migration of neural stem cells

Publication date: Available online 3 January 2017
Source:Neurobiology of Aging
Author(s): Samrat Baral, Ramesh Pariyar, Jaehyo Kim, Ho-Sub Lee, Jungwon Seo
Quercetin is a bioactive compound exerting therapeutic effects on in-vivo animal models of neurodegeneration or neurotoxicity. However, the narrow therapeutic dose-range of quercetin has been a point of concern since previous studies have demonstrated that quercetin induces cytotoxicity in vitro. Quercetin is metabolized to quercetin glucuronates such as quercetin-3-O-glucuronide (Q3GA), primarily detected in the plasma and the brain. Here, we examined whether and how quercetin or Q3GA regulates neural stem cells (NSCs) in vivo and in vitro. Immunohistochemistry showed that oral administration of quercetin increased nestin-, DCX-, BrdU/DCX-, and BrdU/NeuN-positive cells in the DG of mice. However, quercetin decreased the viability of human embryonic NSCs in culture, accompanied by decreased Akt phosphorylation and increased cleavage of caspase-3 and PARP. In contrast, Q3GA increased BrdU-positive cell proliferation, Akt phosphorylation and cyclin D1 expression. PI3K/Akt inhibitor LY294002 reversed Q3GA-induced Akt phosphorylation and cyclin D1 expression, thereby reducing Q3GA-induced proliferation. Furthermore, Q3GA increased the protein secretion of BDNF and its blockade using anti-BDNF antibody reversed Q3GA-induced proliferation. Under differentiation state, Q3GA promotes NSC migration, along with increased mRNA expression of CXCR4. Moreover, Q3GA significantly reversed scopolamine-induced reduction of Akt phosphorylation in the mouse hippocampus and ameliorated scopolamine-induced memory impairments. Our results demonstrate that quercetin and its metabolite Q3GA control NSC viability in a converse manner through contrary regulation of Akt, accounting for the conflicting effects of quercetin in vivo and in vitro. This study provides a novel mechanism for the positive effects of Q3GA on neurogenesis and suggests its therapeutic potential in neurodegenerative diseases.

Graphical abstract

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Abnormal vocal behavior predicts executive and memory deficits in Alzheimer’s disease

Publication date: Available online 3 January 2017
Source:Neurobiology of Aging
Author(s): Kamalini G. Ranasinghe, Jeevit S. Gill, Hardik Kothare, Alexander J. Beagle, Danielle Mizuiri, Susanne M. Honma, Maria Luisa Gorno-Tempini, Bruce L. Miller, Keith A. Vossel, Srikantan S. Nagarajan, John F. Houde
Speakers respond automatically and rapidly to compensate for brief perturbations of pitch in their auditory feedback. The specific adjustments in vocal output require integration of brain regions involved in speech-motor-control in order to detect the sensory-feedback-error and implement the motor-correction. Cortical regions involved in the pitch-reflex phenomenon are highly vulnerable targets of network disruption in Alzheimer's disease (AD). We examined the pitch-reflex in AD patients (n=19) compared to an age-matched control group (n=16). We measured the degree of behavioral compensation (peak-compensation) and the extent of the adaptive response (pitch-response-persistence). Healthy-controls reached a peak-compensation of 18.7±0.8 cents, and demonstrated a sustained compensation at 8.9±0.69 cents. AD patients, in contrast, demonstrated a significantly elevated peak-compensation (22.4±1.2 cents, P<0.05), and a reduced sustained response (pitch-response-persistence, 4.5±0.88 cents, P<0.001). The degree of increased peak-compensation predicted executive dysfunction, while the degree of impaired pitch-response-persistence predicted memory dysfunction, in AD patients. The current study demonstrates pitch-reflex as a sensitive behavioral index of impaired prefrontal modulation of sensorimotor integration, and compromised plasticity mechanisms of memory, in AD.



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The retromer complex system in a transgenic mouse model of AD: influence of age

Publication date: Available online 3 January 2017
Source:Neurobiology of Aging
Author(s): Jin Chu, Domenico Praticò
Deficiencies of the retrograde transport mediated by the retromer complex have been described in Alzheimer's disease (AD). Genetic manipulation of retromer modulates brain amyloidosis in Tg2576 mice. However, whether the complex is altered during the development of the AD-like phenotype remains unknown.In this study we assayed the expression levels of the vacuolar sorting protein 35 (VPS35), VPS26, VPS29, and its cargo proteins, CI-MRP, SorLA in brains of Tg2576 and controls at 3, 8 and 14 months of age. While cortex showed an age-dependent decrease in all but VPS29, levels of the same proteins in the cerebellum were unchanged at any age. Neuronal cells expressing human APP Swedish mutant had also reduced retromer complex levels. However, incubation with a pharmacological chaperone dose-dependently restored these levels together with a reduction in Aβ.Our study is the first to show that in a transgenic mouse model of AD the changes in the expression levels of the retromer complex are age and region-dependent, and that the complex is a viable therapeutic target since its deficiency can be restored pharmacologically by a retromer chaperone.



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