Optimizing power to track brain degeneration in Alzheimer's disease and mild cognitive impairment with tensor-based morphometry: An ADNI study of 515 subjects

Tensor-based morphometry (TBM) is a powerful method to map the 3D profile of brain degeneration in Alzheimer's disease (AD) and mild cognitive impairment (MCI). We optimized a TBM-based image analysis method to determine what methodological factors, and which image-derived measures, maximize statistical power to track brain change. 3D maps, tracking rates of structural atrophy over time, were created from 1030 longitudinal brain MRI scans (1-year follow-up) of 104 AD patients (age: 75.7 ± 7.2 years; MMSE: 23.3 ± 1.8, at baseline), 254 amnestic MCI subjects (75.0 ± 7.2 years; 27.0 ± 1.8), and 157 healthy elderly subjects (75.9 ± 5.1 years; 29.1 ± 1.0), as part of the Alzheimer's Disease Neuroimaging Initiative (ADNI). To determine which TBM designs gave greatest statistical power, we compared different linear and nonlinear registration parameters (including different regularization functions), and different numerical summary measures derived from the maps. Detection power was greatly enhanced by summarizing changes in a statistically-defined region-of-interest (ROI) derived from an independent training sample of 22 AD patients. Effect sizes were compared using cumulative distribution function (CDF) plots and false discovery rate methods. In power analyses, the best method required only 48 AD and 88 MCI subjects to give 80% power to detect a 25% reduction in the mean annual change using a two-sided test (at α = 0.05). This is a drastic sample size reduction relative to using clinical scores as outcome measures (619 AD/6797 MCI for the ADAS-Cog, and 408 AD/796 MCI for the Clinical Dementia Rating sum-of-boxes scores). TBM offers high statistical power to track brain changes in large, multi-site neuroimaging studies and clinical trials of AD.     

Signal abnormalities on 1.5 and 3 Tesla brain MRI in multiple sclerosis patients and healthy controls. A morphological and spatial quantitative comparison study

Previous studies in patients with multiple sclerosis (MS) revealed increased lesion count and volume on 3 T compared to 1.5 T. Morphological and spatial lesion characteristics between 1.5 T and 3 T have not been examined. The aim of this study was to investigate the effect of changing from a 1.5 T to a 3 T MRI scanner on the number, volume and spatial distribution of signal abnormalities (SA) on brain MRI in a sample of MS patients and normal controls (NC), using pair- and voxel-wise comparison procedures. Forty-one (41) MS patients (32 relapsing-remitting and 9 secondary-progressive) and 38 NC were examined on both 1.5 T and 3 T within one week in random order. T2-weighted hyperintensities (T2H) and T1-weighted hypointensities (T1H) were outlined semiautomatically by two operators in a blinded fashion on 1.5 T and 3 T images. Spatial lesion distribution was assessed using T2 and T1 voxel-wise SA probability maps (SAPM). Pair-wise analysis examined the proportion of SA not simultaneously outlined on 1.5 T and 3 T. A posteriori unblinded analysis was conducted to examine the non-overlapping identifications of SA between the 1.5 T and 3 T. For pair-wise T2- and T1-analyses, a higher number and individual volume of SA were detected on 3 T compared to 1.5 T (p < 0.0001) in both MS and NC. Logistic regression analysis showed that the likelihood of missing SA on 1.5 T was significantly higher for smaller SA in both MS and NC groups. SA probability map (SAPM) analysis revealed significantly more regionally distinct spatial SA differences on 3 T compared to 1.5 T in both groups (p < 0.05); these were most pronounced in the occipital, periventricular and cortical regions for T2H. This study provides important information regarding morphological and spatial differences between data acquired using 1.5 T and 3 T protocols at the two scanner field strengths.     

脑白质高信号和多发性腔隙性梗死的步态障碍特点及其与认知功能的相关性研究

目的研究脑白质高信号(WMH)和多发性腔隙性梗死(LI)的步态障碍特点及其与认知功能的相关性。方法选取本院神经内科门诊及住院的31例可能源于血管因素的WMH患者为WMH组,28例多发性LI患者为LI组,另选取性别、年龄匹配的健康人26例为NC组。采用多种量表评估总体认知功能及情绪障碍;通过TUG试验、Berg平衡量表(BBS)测评步态的移动性及稳定性;采用IDEEA记录仪记录步态参数。比较三组的认知功能与步态参数,对WMH组和LI组患者的步态特点与认知功能的关系进行相关性分析。结果WMH组和LI组的总体认知功能评分均低于NC组(P<0.05);WMH组的定向、记忆、注意、执行、计算评分均低于NC组(P<0.05);LI组的记忆、执行评分低于NC组(P<0.05);WMH组的定向、记忆、计算评分均低于LI组(P<0.05)。WMH组较NC组TUG试验时间显著延长,平衡功能下降,步长缩短,步速减慢,步频减少(P<0.05);LI组较NC组TUG试验时间显著延长,平衡功能下降(P<0.05),步长、步速、步频无显著差异(P>0.05);与LI组相比,WMH组步长缩短,步速下降更明显(P<0.01)。WMH组中,步长与执行功能呈显著正相关(P=0.025);LI组中,步长与注意功能呈显著正相关(P=0.012)。结论WMH影响步态的移动性和稳定性,LI主要影响步态的稳定性;WMH步态障碍与执行功能受损有关,LI步态障碍与注意功能受损有关。     

Multidimensional classification of hippocampal shape features discriminates Alzheimer's disease and mild cognitive impairment from normal aging

We describe a new method to automatically discriminate between patients with Alzheimer's disease (AD) or mild cognitive impairment (MCI) and elderly controls, based on multidimensional classification of hippocampal shape features. This approach uses spherical harmonics (SPHARM) coefficients to model the shape of the hippocampi, which are segmented from magnetic resonance images (MRI) using a fully automatic method that we previously developed. SPHARM coefficients are used as features in a classification procedure based on support vector machines (SVM). The most relevant features for classification are selected using a bagging strategy. We evaluate the accuracy of our method in a group of 23 patients with AD (10 males, 13 females, age ± standard-deviation (SD) = 73 ± 6 years, mini-mental score (MMS) = 24.4 ± 2.8), 23 patients with amnestic MCI (10 males, 13 females, age ± SD = 74 ± 8 years, MMS = 27.3 ± 1.4) and 25 elderly healthy controls (13 males, 12 females, age ± SD = 64 ± 8 years), using leave-one-out cross-validation. For AD vs controls, we obtain a correct classification rate of 94%, a sensitivity of 96%, and a specificity of 92%. For MCI vs controls, we obtain a classification rate of 83%, a sensitivity of 83%, and a specificity of 84%. This accuracy is superior to that of hippocampal volumetry and is comparable to recently published SVM-based whole-brain classification methods, which relied on a different strategy. This new method may become a useful tool to assist in the diagnosis of Alzheimer's disease.     

Image derived input functions for dynamic High Resolution Research Tomograph PET brain studies

The High Resolution Research Tomograph (HRRT) is a dedicated human brain positron emission tomography (PET) scanner. The aim of the present study was to validate the use of image derived input functions (IDIF) as an alternative for arterial sampling for HRRT human brain studies. To this end, IDIFs were extracted from 3D ordinary Poisson ordered subsets expectation maximization (OP-OSEM) and reconstruction based partial volume corrected (PVC) OP-OSEM images.IDIFs, either derived directly from regions of interest or further calibrated using manual samples taken during scans, were evaluated for dynamic [¹¹C]flumazenil data (n = 6). Results obtained with IDIFs were compared with those obtained using blood sampler input functions (BSIF). These comparisons included areas under the curve (AUC) for peak (0–3.3 min) and tail (3.3–55.0 min). In addition, slope, intercept and Pearson's correlation coefficient of tracer kinetic analysis results based on IDIF and BSIF were calculated for each subject.Good peak AUC ratios (0.83 ± 0.21) between IDIF and BSIF were found for calibrated IDIFs extracted from OP-OSEM images. This combination of IDIFs and images also provided good slope values (1.07 ± 0.11). Improved resolution, as obtained with PVC OP-OSEM, changed AUC ratios to 1.14 ± 0.35 and, for tracer kinetic analysis, slopes changed to 0.95 ± 0.13. For all reconstructions, non-calibrated IDIFs gave poorer results (> 61 ± 34% higher slopes) compared with calibrated IDIFs.The results of this study indicate that the use of IDIFs, extracted from OP-OSEM or PVC OP-OSEM images, is feasible for dynamic HRRT data, thereby obviating the need for online arterial sampling.     

帕金森病轻度认知功能障碍:基于体素的全脑灰质形态学研究

目的采用基于体素的形态学测量方法,分析帕金森病(PD)伴轻度认知功能损害(MCI)患者全脑灰质结构的变化。方法利用3.0T MR仪对22例伴MCI的PD患者(PD伴MCI组)、21例认知功能正常的PD患者(单纯PD组)及20名健康对照(NC组)进行T1W扫描。采用SPM8为基础的VBM8工具箱进行数据处理。结果与NC组比较,PD伴MCI组脑灰质萎缩见于双侧额叶、左侧颞叶、双侧枕叶、双侧小脑、左侧后扣带回及左侧海马区域;单纯PD组脑灰质萎缩集中出现于左侧额叶、颞叶。与单纯PD组相比,PD伴MCI组左侧颞中回和海马旁回出现灰质萎缩。结论伴有MCI的PD患者的脑灰质结构改变范围比不伴MCI者更广,提示PD患者认知功能改变存在脑形态结构水平的异常。     

Optimized preparation of vinpocetine proliposomes by a novel method and in vivo evaluation of its pharmacokinetics in New Zealand rabbits

Free-flowing proliposomes which contained vinpocetine were prepared successfully to increase the oral bioavailability of vinpocetine. In this study the proliposomes were prepared by a novel method which was reported for the first time and the formulation was optimized using the centre composite design (CCD). The optimized formulation was Soybean phosphatidylcholine: 860 mg; cholesterol: 95 mg and sorbitol: 8000 mg. After the proliposomes were contacted with water, the suspension of vinpocetine liposomes formed automatically and the entrapment efficiency was approximately 86.3% with an average particle size of about 300 nm. The physicochemical properties of the proliposomes including SEM, TEM, XRD and FTIR were also detected. HPLC system was applied to study the concentration of vinpocetine in the plasma of the New Zealand rabbits after oral administration of vinpocetine proliposomes and vinpocetine suspension. The pharmacokinetic parameters were calculated by the software program DAS2.0. The concentration–time curves of vinpocetine suspension and vinpocetine proliposomes were much more different. There were two absorption peaks on the concentration–time curves of the vinpocetine proliposomes. The pharmacokinetic parameters of vinpocetine and vinpocetine proliposomes in New Zealand rabbits were T_max 1 h and 3 h (there was also an absorption peak at 1 h); C_max 163.82 ± 12.28 ng/ml and 166.43 ± 21.04 ng/ml; AUC_0 − ∞ 1479.70 ± 68.51 ng/ml h and 420.70 ± 35.86 ng/ml h, respectively. The bioavailability of vinpocetine in proliposomes was more than 3.5 times higher than the vinpocetine suspension. The optimized vinpocetine proliposomes did improve the oral bioavailability of vinpocetine in New Zealand rabbits and offer a new approach to enhance the gastrointestinal absorption of poorly water soluble drugs.     

Neural substrates of letter fluency processing in young adults who were born very preterm: Alterations in frontal and striatal regions

Several studies have described poorer performance in executive-type tasks in individuals who were born very preterm compared to controls. As there is evidence that high-order executive functions may be underpinned by neuronal activity in frontal–striatal circuits, we investigated with functional MRI a group of young adults who were born very preterm (n = 28, gestational age < 33 weeks) and controls (n = 26) in order to detect possible alterations in brain activation during completion of a letter fluency task with differential cognitive loading (“easy” and “hard” letter trials). Structural MRI data were also collected to clarify whether any functional changes were associated with structural brain volume changes. Group membership, level of task difficulty and gestational age had significant effects on brain activation. In the absence of significant between-group differences in task performance, during “easy” letter trials, very preterm-born individuals showed attenuated activation in anterior cingulate gyrus, right caudate nucleus and left inferior frontal gyrus compared to controls. During “hard” letter trials, very preterm-born individuals showed both decreased and increased BOLD signal compared to controls, in left middle frontal and anterior cingulate gyrus, respectively. BOLD signal in caudate nucleus and anterior cingulate gyrus, in regions with peaks close to areas where between-group differences were observed, was linearly associated with gestational age. Analysis of structural MRI data showed altered grey matter distribution in the preterm-born group compared to controls. However, fMRI results were only partly explained by structural changes, and may reflect processes of functional plasticity for the successful completion of executive-type operations.     

Task complexity relates to activation of cortical motor areas during uni- and bimanual performance: A functional NIRS study

Hand motor tasks are frequently used to assess impaired motor function in neurology and neurorehabilitation. Assessments can be varied by means of hand laterality, i.e. unimanual or bimanual performance, as well as by means of task complexity, i.e. different degrees ranging from simple to complex sequence tasks. The resulting functional activation in human primary motor cortex (M1) has been studied intensively by traditional neuroimaging methods.Previous studies using functional near-infrared spectroscopy (fNIRS) investigated simple hand motor tasks. However, it is unknown whether fNIRS can also detect changes in response to increasing task complexity. Our hypothesis was to show that fNIRS could detect activation changes in relation to task complexity in uni- and bimanual tasks.Sixteen healthy right-handed subjects performed five finger-tapping tasks: unimanual left and right, simple and complex tasks as well as bimanual complex tasks. We found significant differences in oxy-hemoglobin (O₂Hb) and deoxy-hemoglobin (HHb) concentration in the right hemisphere over M1. Largest O₂Hb concentration changes were found during complex (0.351 ± 0.051 μmol/l) and simple (0.275 ± 0.054 μmol/l) right hand tasks followed by bimanual (0.249 ± 0.047 μmol/l), complex (0.154 ± 0.034 μmol/l) and simple (0.110 ± 0.034 μmol/l) left hand tasks. Largest HHb concentration changes were found during bimanual (− 0.138 ± 0.006 μmol/l) tasks, followed by simple right hand (− 0.12 ± 0.016 μmol/l), complex left (− 0.0875 ± 0.007 μmol/l), complex right (− 0.0863 ± 0.005 μmol/l) and simple left (− 0.0674 ± 0.005 μmol/l) hand tasks.We report for the first time that fNIRS detects oxygenation changes in relation to task complexity during finger-tapping. The study aims to contribute to the establishment of fNIRS as a neuroimaging method to assess hand motor function in clinical settings where traditional neuroimaging methods cannot be applied.     

Abdominal visceral fat accumulation is associated with hippocampus volume in non-dementia patients with type 2 diabetes mellitus

Obesity is associated with cognitive dysfunction, for which changes in the hippocampus plausibly play a pivotal role. We tested the hypothesis that an elevated level of visceral fat accumulation (VFA) correlates with hippocampus volume and insulin resistance in non-dementia patients with type 2 diabetes.Subjects included 48 non-dementia patients with type 2 diabetes, who were divided into two groups, high VFA group (mean ± standard deviation: age = 65 ± 6 years, n = 30) and normal VFA group (65 ± 5 years, n = 18). Hippocampus volume has been quantitated with computer-assisted analysis using a magnetic resonance imaging (MRI) voxel-based specific regional analysis system developed for the study of Alzheimer's disease (VSRAD), which yields a Z-score as the end point for assessment of hippocampal volume. The Z-score was higher in the high VFA group than in the normal VFA group (p < 0.0001). The fasting plasma glucose (p < 0.05) and insulin concentrations (p < 0.0001) and the homeostasis model assessment (HOMA) index (p < 0.0001) were higher in the high VFA group than in the normal VFA group. Multiple regression analysis showed that VFA levels were independently predicted by Z-score and HOMA index.Our results indicate that the elevated level of VFA in Japanese non-dementia patients with type 2 diabetes is characterized by increased hippocampus volume and insulin resistance, and that the Z-score and HOMA index are independent predictors of VFA.     

The QUASAR reproducibility study, Part II: Results from a multi-center Arterial Spin Labeling test–retest study

Arterial Spin Labeling (ASL) is a method to measure perfusion using magnetically labeled blood water as an endogenous tracer. Being fully non-invasive, this technique is attractive for longitudinal studies of cerebral blood flow in healthy and diseased individuals, or as a surrogate marker of metabolism. So far, ASL has been restricted mostly to specialist centers due to a generally low SNR of the method and potential issues with user-dependent analysis needed to obtain quantitative measurement of cerebral blood flow (CBF).Here, we evaluated a particular implementation of ASL (called Quantitative STAR labeling of Arterial Regions or QUASAR), a method providing user independent quantification of CBF in a large test–retest study across sites from around the world, dubbed “The QUASAR reproducibility study”. Altogether, 28 sites located in Asia, Europe and North America participated and a total of 284 healthy volunteers were scanned. Minimal operator dependence was assured by using an automatic planning tool and its accuracy and potential usefulness in multi-center trials was evaluated as well.Accurate repositioning between sessions was achieved with the automatic planning tool showing mean displacements of 1.87 ± 0.95 mm and rotations of 1.56 ± 0.66°. Mean gray matter CBF was 47.4 ± 7.5 [ml/100 g/min] with a between-subject standard variation SD_b = 5.5 [ml/100 g/min] and a within-subject standard deviation SD_w = 4.7 [ml/100 g/min]. The corresponding repeatability was 13.0 [ml/100 g/min] and was found to be within the range of previous studies.     

Investigating the benefits of multi-echo EPI for fMRI at 7 T

Functional MRI studies on humans with BOLD contrast are increasingly performed at high static magnetic field in order to exploit the increased sensitivity. The downside of high-field fMRI using the gradient-echo echo-planar imaging (GE-EPI) method is that images are typically very strongly affected by image distortion and signal loss. It has been demonstrated at 1.5 T and 3 T that image artifacts can be reduced and functional sensitivity simultaneously increased by the use of parallel-accelerated multi-echo EPI. Using sensitivity measurements and an activation study with a cognitive Stroop task experiment (N = 7) we here investigate the potential of this method at 7 T. The main findings are: (a) image quality compared to a conventional acquisition scheme is drastically improved; (b) according to CNR estimations the average BOLD sensitivity increases by 6.1 ± 4.3% and 13.9 ± 5.5% for unweighted and CNR-weighted echo summation, respectively; (c) both functional signal changes and sensitivity in the multi-echo data do not exhibit a pronounced dependence on TE. The consequence is that (d) in practice the performance of simple echo summation at very high field is comparable to that based on a CNR filter. Finally, (e) temporal noise observed in the different echo time courses is not strongly correlated, thus explaining why echo summation is advantageous.The results at typical spatial resolution show that multi-echo EPI acquisition leads to considerable artifact reduction and sensitivity gains, making it superior to conventional GE-EPI for fMRI at 7 T.     

Anti-NR2 glutamate receptor antibodies as an early biomarker of cerebral small vessel disease

ObjectivesCerebral small vessel disease (SVD) associated with age and vascular risk factors is one of the leading causes of cognitive disorders as well as ischemic and hemorrhagic strokes. The pathogenesis of this disease has not been fully understood yet. The previously established association of the antibodies against the NR2 subunit of the NMDA receptor (NR2ab) with the mechanisms of SVD such as ischemia and blood–brain barrier (BBB) disruption, might suggest their importance in the brain damage.Design & methodsWe studied the NR2ab serum level in 70 patients (45 females, 61.1 ± 6.3 y.o.) with different severity of cognitive impairment and MRI features of SVD and 20 healthy volunteers (12 females, 58.5 ± 6.4 y.o.).ResultsThe elevated level of NR2ab was associated with subjective cognitive impairment (SCI) (p = 0.028) and mild cognitive impairment (MCI) (p = 0.017), Fazekas grade (F) 2 (p = 0,002) and F3 (p = 0,009) of white matter hyperintensities (WMH) and the numbers of lacunes in the cerebral white matter (less than 5) (p = 0,039).ConclusionThe detected increase in serum NR2ab level in patients with SCI, as well as the minimal amount of white matter lacunes, is most likely caused by hypoxia-induced endothelial damage in the early stage of SVD. Normal NR2ab values in patients with F1 WMH, the increased NR2ab level in patients with F2 and F3 WMH and those with the minimal number of lacunes can indicate that NR2bs are involved in diffuse brain damage due to hypoxia-induced loss of BBB integrity.     

Skin vasoreactivity to insulin iontophoresis is reduced in elderly subjects and is absent in treated non-insulin-dependent diabetes patients

We investigated the skin vasoreactivity to insulin in normal subjects and in treated non-insulin-dependent diabetes mellitus (NIDDM) patients. We measured cutaneous perfusion by laser-Doppler flowmetry (LDF) at rest and during skin cathodal iontophoresis (six pulses of 0.1 mA each for 20 s, with 40 s interval between stimulations) of insulin (0.1 ml Humulin R 100 IU/ml diluted 1/10 with of 0.9% saline solution) in 45 healthy subjects (HS), (25 males, 20 females, aged 45 ± 18 years), and in 15 treated NIDDM patients (13 males), aged 66 ± 8 years. Fifteen of the HS were used as controls. In these 15 sex- and age-matched HS and in the patients, we assessed also the skin postischemic hyperemia by LDF. In HS cutaneous blood flux response (CBF) to iontophoresis of insulin in saline (expressed as percent changes from baseline) was significantly higher than CBF response to iontophoresis of pure saline (maximum response: 360 ± 51% versus 172 ± 42%, respectively; P < 0.001, ANOVA for repeated measures). The maximum “net” CBF response to insulin (response to insulin minus response to saline) showed a negative correlation (r = –0.361; P < 0.01) with age in HS, and resulted significantly lower in the oldest than in the youngest HS (105 ± 40% versus 307 ± 45%, respectively; P < 0.01). No significant correlation was observed between the maximum CBF response to saline and the age of subjects. In NIDDM patients the “net” CBF response to insulin iontophoresis resulted significantly lower than in 15 sex- and age-matched control subjects (maximum response: –50 ± 89% versus 201 ± 81%, respectively; P < 0.001, ANOVA for repeated measures). No significant difference was observed between diabetics and controls, nor in basal perfusion (6.5 ± 1.3 IU versus 6.8 ± 1.7 IU, respectively) neither in the skin postischemic hyperemia (250 ±14% versus 258 ± 27%, respectively). These results confirm that insulin iontophoresis induces a skin vasodilatatory effect in normal subjects and show that this effect is reduced by aging and is absent in treated NIDDM patients. The local skin vasodilatatory effect induced by insulin seems to involve mechanisms different from those underlying the skin postischemic hyperemia.     

Mapping the effect of APOE ε4 on gray matter loss in Alzheimer's disease in vivo

Previous studies suggest that in Alzheimer's disease (AD) the Apolipoprotein E (APOE) ε4 allele is associated with greater vulnerability of medial temporal lobe structures. However, less is known about its effect on the whole cortical mantle. Here we aimed to identify APOE-related patterns of cortical atrophy in AD using an advanced computational anatomy technique. We studied 15 AD patients carriers (ε4+, age: 72 ± 10 SD years, MMSE: 20 ± 3 SD) and 14 non-carriers (ε4−, age: 69 ± 9, MMSE: 20 ± 5) of the ε4 allele and compared them to 29 age-and-sex matched controls (age: 70 ± 9, MMSE: 28 ± 1). Each subject underwent a clinical evaluation, a neuropsychological battery, and high-resolution MRI. UCLA's cortical pattern matching technique was used to identify regions of local cortical atrophy. ε4+ and ε4− patients showed similar performance on neuropsychological tests (p > .05, t-test). Diffuse cortical atrophy was detected for both ε4+ (p = .0001, permutation test) and ε4− patients (p = .0001, permutation test) relative to controls, and overall gray matter loss was about 15% in each patients group. Differences in gray matter loss between carriers and non-carriers mapped to the temporal cortex and right occipital pole (20% greater loss in carriers) and to the posterior cingulate, left orbitofrontal and dorsal fronto-parietal cortex (5–15% greater loss in non-carriers). APOE effect in AD was not significant (p > .74, ANOVA), but a significant APOE by region (temporal vs fronto-parietal cortex) interaction was detected (p = .002, ANOVA), in both early and late-onset patients (p < .05, ANOVA). We conclude that the ε4 allele modulates disease phenotype in AD, being associated with a pattern of differential temporal and fronto-parietal vulnerability.     

Triggered release of siRNA from poly(ethylene glycol)-protected, pH-dependent liposomes

The ability of small interfering RNA (siRNA) to regulate gene expression has potential therapeutic applications, but its use is limited by inefficient delivery. Triggered release of adsorbed poly(ethylene glycol) (PEG)-b-polycation polymers from pH-dependent (PD) liposomes enables protection from immune recognition during circulation (pH 7.4) and subsequent intracellular delivery of siRNA within the endosome (pH ~5.5). Polycationic blocks, based on either poly[2-(dimethylamino)ethyl methacrylate] (31 or 62 DMA repeat units) or polylysine (21 K repeat units), act as anchors for a PEG (113 ethylene glycol repeat units) protective block. Incorporation of 1,2-dioleoyl-3-dimethylammonium-propane (DAP), a titratable lipid, increases the liposome's net cationic character within acidic environments, resulting in polymer desorption and membrane fusion. Liposomes encapsulating siRNA demonstrate green fluorescent protein (GFP) silencing in genetically-modified, GFP-expressing HeLa cells and glyceraldehyde-3-phosphate dehydrogenase (GAPD) knockdown in human umbilical vein endothelial cells (HUVEC). Bare and PD liposomes coated with PEG113-DMA31 exhibit a 0.16 ± 0.2 and 0.32 ± 0.3 fraction of GFP knockdown, respectively. In contrast, direct siRNA administration and Oligofectamine complexed siRNA reduce GFP expression by 0.06 ± 0.02 and 0.14 ± 0.02 fractions, respectively. Our in vitro data indicates that polymer desorption from PD liposomes enhances siRNA-mediated gene knockdown.     

Effects of large volume, ice-cold intravenous fluid infusion on respiratory function in cardiac arrest survivors

International guidelines for cardiopulmonary resuscitation recommend mild hypothermia (32–34 °C) for 12–24 h in comatose survivors of cardiac arrest. To induce therapeutic hypothermia a variety of external and intravascular cooling devices are available. A cheap and effective method for inducing hypothermia is the infusion of large volume, ice-cold intravenous fluid. There are concerns regarding the effects of rapid infusion of large volumes of fluid on respiratory function in cardiac arrest survivors. We have retrospectively studied the effects of high volume cold fluid infusion on respiratory function in 52 resuscitated cardiac arrest patients.The target temperature of 32–34 °C was achieved after 4.1 ± 0.5 h (cooling rate 0.48 °C/h). During this period 3427 ± 210 mL ice-cold fluid was infused. Despite significantly reduced LV-function (EF 35.8 ± 2.2%) the respiratory status of these patients did not deteriorate significantly. On intensive care unit admission the mean PaO₂ was 231.4 ± 20.6 mmHg at a F_iO₂ of 0.82 ± 0.03 (PaO₂/F_iO₂ = 290.0 ± 24.1) and a PEEP level of 7.14 ± 0.31 mbar. Until reaching the target temperature of ≤34 °C the F_iO₂ could be significantly reduced to 0.63 ± 0.03 with unchanged PEEP level (7.23 ± 0.36 mbar). Under these conditions the PaO₂/F_iO₂ ratio slightly decreased to 247.5 ± 18.5 (P = 0.0893). Continuing the saline infusion to achieve a body temperature of 33 °C, the F_iO₂ could be further reduced with unchanged PEEP.The infusion of large volume, ice-cold fluid is an effective and inexpensive method for inducing therapeutic hypothermia. Resuscitation from cardiac arrest is associated with a deterioration in respiratory function. The infusion of large volumes of cold fluid does not cause a statistically significant further deterioration in respiratory function. A larger, randomized and prospective study is required to assess the efficacy and safety of ice-cold fluid infusion for the induction of therapeutic hypothermia.     

Antitumor activity of EGFR targeted pH-sensitive immunoliposomes encapsulating gemcitabine in A549 xenograft nude mice

Immunoliposomes directed by monoclonal antibodies are promising vehicles for tumor targeted drug delivery. Development of a long-circulating formulation of pH-sensitive liposomes (PSLs) with epidermal growth factor receptor (EGFR) antibody attached was designed and tested using A549 cells and BALB/c-nu/nu mouse tumor model. PSL formulation was prepared using small unilamellar vesicles of DOPE and CHEMS (6:4 molar ratio) by REV method. The average size and zeta-potential of the formulation measured by dynamic laser-light scattering were approximately 146 ± 43.9 nm (PDI = 0.09 ± 0.02) and − 1.77 ± 0.03 mV, respectively. A549 cells were xenotransplanted into BALB/c-nu/nu mice and various formulations of gemcitabine (gem), such as in its free form, PSLs or Ab-PSLs, were injected intravenously via a tail vein. The rate of tumor volume increment in Ab-PSLs with gem-treated group was remarkably slower than that of other drug-treated group. The tumor from Ab-PSLs with gem 160 mg/kg-injected group exhibited a markedly lowest account of PCNA labeled cells and had highest TUNEL-positive cells among tested. This suggests that treatment of Ab-PSLs with gem resulted in an increased apoptosis of tumor cells, leading to tumor growth inhibition. These results demonstrate that PSLs provide an efficient and targeted delivery of gemcitabine and may represent a useful new treatment approach for tumors which overexpress the EGFR.     

基于Adaboost的轻度认知障碍和阿尔茨海默病分类

目的 采用Adaboost集成分类方法区分轻度认知障碍(MCI)、阿尔茨海默病(AD)患者与正常对照(NC)的功能与结构磁共振成像数据.方法 对26例MCI患者(MCI组)、26例AD患者(AD组)及30名健康老年人(NC组)的MRI图像进行分析,选择双侧海马体积及3组间存在显著差异脑区的低频振幅值(ALFF)作为分类特征,采用Adaboost集成分类器对3组被试进行两两分类,利用留一交叉验证估算分类准确率.结果 增加性别、年龄和MMSE特征后,Adaboost集成分类方法对AD与MCI、MCI与NC、AD与NC分类准确率分别达98.08%、80.36%和100%.结论 Adaboost集成分类方法可较好地区分MCI、AD与NC.     

帕金森病MRI白质高信号研究

目的 探讨帕金森病（PD）常规MRI检查白质高信号（WMH）与临床的关系.方法 分析64例 PD患者和45例健康老年人对照组常规MRI检查WMH、脑室周高信号（PVH）、深部白质高信号（DWMH）和年龄、病程、分级的关系.结果 PD患者WMH发生率较对照组增高，但无显著性差异（ P＞0.05），有WMH的PD患者较无WMH的患者年龄更大（ P＜0.01），病情更严重（ P〈0.01）但病程无显著性差异（ P＞0.05）;PD组DWMH发生率较对照组略高，但无显著性差异（ P＞0.05）;有DWMH的PD患者较无DWMH的患者年龄更大（ P〈0.01），但病程、病情严重程度无显著性差异（ P＞0.05）;PD组PVH发生率较对照组增高，有显著性差异（ P〈0.05），有PVH的PD患者较无PVH的患者年龄更大（ P〈0.01），病情更严重（ P〈0.01），但病程无显著性差异（ P＞0.05）; PD患者和对照组的DWMH分级无显著性差异（ P＞0.05），但PVH分级有显著性差异（ P〈0.05）.结论 PVH与PD的一些临床特征有关，PVH可能会影响病情的严重程度。