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Normal ageing is associated with gradual brain atrophy. Determining spatial and temporal patterns of change can help shed light on underlying mechanisms. Neuroimaging provides various measures of brain structure that can be used to assess such age-related change but studies to date have typically considered single imaging measures. Although there is consensus on the notion that brain structure deteriorates with age, evidence on the precise time course and spatial distribution of changes is mixed. We assessed grey matter (GM) and white matter (WM) structure in a group of 66 adults aged between 23 and 81. Multimodal imaging measures included voxel-based morphometry (VBM)-style analysis of GM and WM volume and diffusion tensor imaging (DTI) metrics of WM microstructure. We found widespread reductions in GM volume from middle age onwards but earlier reductions in GM were detected in frontal cortex. Widespread age-related deterioration in WM microstructure was detected from young adulthood onwards. WM decline was detected earlier and more sensitively using DTI-based measures of microstructure than using markers of WM volume derived from conventional T1-weighted imaging.
Studying the distribution and time course of alterations that occur in the normal brain with ageing is important for understanding the mechanisms leading to these changes and for better characterising neurological disorders whose risk increases with advancing age (e.g., dementia). Magnetic resonance imaging (MRI) studies have been particularly important in this regard (Anderson et al., 2005; Galluzzi et al., 2008; Sullivan and Pfefferbaum, 2007).
The advent of quantitative techniques based on the analyses of MRI structural data, such as Voxel-Based Morphometry (VBM) and volumetric analyses, has allowed a sensitive detection of regional patterns of grey matter (GM) and white matter (WM) volume loss. GM volume reduction begins in early adulthood and continues approximately linearly throughout adulthood (Ge et al., 2002; Lehmbeck et al., 2006; Sowell et al., 2003; Walhovd et al., 2005). By contrast, total WM volume change is characterised by a nonlinear relationship with age, with an increase until approximately the fifth decade of life and a decline thereafter (Bartzokis et al., 2001; Pfefferbaum et al., 1994; Salat et al., 1999; Sowell et al., 2003; Walhovd et al., 2005).
More recently, diffusion tensor imaging (DTI) has been used to quantify alterations in WM microstructure during ageing (Abe et al., 2002; Ardekani et al., 2007; Bhagat and Beaulieu, 2004; Head et al., 2004; Madden et al., 2004; O'Sullivan et al., 2001; Ota et al., 2006; Pfefferbaum et al., 2005, 2000; Pfefferbaum and Sullivan, 2003; Salat et al., 2005a,b, 2008; Sullivan et al., 2006; Virta et al., 1999). By fitting a model (the diffusion tensor) to the MRI diffusion data at each brain voxel, this technique allows us to estimate important parameters such as fractional anisotropy (FA: a measure of the degree of diffusion directionality), mean diffusivity (MD), and the three diffusivities (parallel and two perpendicular) of the diffusion tensor (Basser, 1995; Pierpaoli and Basser, 1996). Diffusion metrics are sensitive to age-related changes, but in some cases the correspondence between changes detected using DTI and conventional volume or VBM measurements is not clear.
In the current study we used VBM and DTI measures of GM and WM to study age-related effects on brain structure in a population of healthy adult subjects. We aimed to determine the timing and spatial distribution of age-related changes using a range of volumetric and DTI-based measures.
MRI data were acquired in a group of 66 healthy subjects (31 males, 35 females, median age = 36.7 years, range = 23.0-81.6 years, all right-handed). We tested for linear and nonlinear relationships between brain structure and age (see below) and also performed subgroup analyses for which we divided subjects into young adults (YA) (n = 37, 16 males, 21 females, median age = 29.1, range = 23.0-40.2 years), middle-aged adults (MA) (n = 19, 9 males, 10 females, median age = 48.0, range = 41.0-59.6 years) and older adults (OA) (n = 10, 6 males, 4 females, median age = 67.9, range = 60.0-81.6 years). The ages chosen for defining the different age subgroups are broadly consistent with previous studies in YA (Giorgio et al., 2008; McLaughlin et al., 2007; O'Sullivan et al., 2001; Pfefferbaum et al., 2005; Sullivan et al., 2006), MA (Salat et al., 2005a,b) and OA (McLaughlin et al., 2007; Salat et al., 2005b).
None of the participants had a history of psychiatric or neurological disease or substance abuse. On MRI they did not show overt abnormalities such as infarct, vascular malformation or tumour and none of them had WM lesions. Informed written consent was obtained from all participants according to ethical approval from the Oxfordshire Research Ethics Committee C.
Scans were obtained on a 1.5T Siemens Sonata MR scanner using a standard single-channel head coil with a maximum gradient strength of 40 mT m-1. For the DTI data, two sets of echo-planar images (EPI) of the whole head were acquired (TR = 8500 ms; TE = 80 ms; 53 × 2.5 mm axial slices; in-plane resolution = 2.5 × 2.5 mm2). Each set comprised 3 non-diffusion-weighted and 60 diffusion-weighted images acquired with a b-value of 1000 s mm-2 uniformly distributed across 60 gradient directions. A T1-weighted image was also acquired in each participant for a VBM-style analysis and image registration (3D FLASH, TR = 12 ms, TE = 5.6 ms, 1 mm isotropic voxels, matrix = 256 × 256 × 208, 3 averages, elliptical sampling, coronal orientation). The absence of WM lesions was confirmed on both non-diffusion- weighted and T1-weighted images.
We employed an 'optimised' VBM-style protocol (Good et al., 2001) using FSL (FMRIB Software Library v4.1, www.fmrib.ox.ac.uk/fsl; (Smith et al., 2004)) tools for brain extraction (Smith, 2002) and tissue segmentation (Zhang et al., 2001). FMRIB's Nonlinear Image Registration Tool (FNIRT) (Andersson et al., 2007a,b) was used to spatially register the native images to a standard-space template. The aim was to assess correlations of regional GM and WM volumes with age. The raw T1-weighted images were first segmented to form images representing partial volume estimates of each tissue class (Zhang et al., 2001). For the analysis of GM, the native GM images were affinely registered to the ICBM-152 GM template, mirror images were created flipping the images across the midline and a left–right symmetric study-specific GM template was created from the average of these images. The native GM images were then nonlinearly transformed to this template using FNIRT. The signal in each voxel of the transformed images was modulated by the Jacobian determinant of the nonlinear component of the warp field. This modulation adjusts the signal in each voxel to reflect (or compensate for) the amount of contraction or enlargement due to the nonlinear component of the spatial transformation. All modulated normalised GM volume images were smoothed with an isotropic Gaussian kernel with a sigma of 3.5 mm (~ 8 mm FWHM). To test for linear and nonlinear (quadratic) local correlations between changes in GM volume and age, a regression analysis was performed using age and age2 as regressors. To compare GM volumes between the different age subgroups, unpaired t-tests were used. Statistical inference on all analyses was performed using the randomise programme within FSL, which performs permutation testing (5000 permutations) (Nichols and Holmes, 2002). Thresholding was carried out using TFCE (Threshold-Free Cluster Enhancement), a method for finding significant clusters in MRI data without having to define them in a binary way (Smith and Nichols, 2009). Clusters were assessed for significance at p < 0.05, fully corrected for multiple comparisons across space. Anatomical locations of the significant GM clusters were determined by reference to the Harvard-Oxford cortical structural atlas integrated into FSLView (part of FSL).
For the WM we used a protocol similar to that of the GM (see above). All modulated normalised WM volume images were smoothed with an isotropic Gaussian kernel with a sigma of 4 mm (~ 10 mm FWHM). Anatomical location of the significant WM clusters were determined by reference to an atlas of human WM anatomy (Wakana et al., 2004) integrated into FSLView.
The different levels of smoothing for GM and WM were chosen to be compatible with previous studies (e.g., (Giorgio et al., 2010; Paus et al., 1999; Sowell et al., 1999)).
Diffusion MRI data were pre-processed using DTIFit within the FMRIB Diffusion Toolbox (FDT, part of FSL). Images were corrected for eddy currents and head motion by using affine registration to the non-diffusion volumes (b = 0). Data were averaged across the two acquisitions to improve signal-to-noise ratio. Images of FA, MD, diffusivity parallel (λ1) and perpendicular ((λ2 + λ3)/2) to the principal diffusion direction were obtained. Voxelwise correlations of FA with age and FA comparisons between the different age subgroups were assessed using TBSS (part of FSL (Smith et al., 2006)). FA images were first nonlinearly (using FNIRT) registered to a high resolution standard-space average of 58 well aligned good quality FA images from healthy subjects and then averaged. The average of the data was thinned to create a 'skeleton' of WM, representing the tracts common to all subjects. This WM tract skeleton was thresholded at FA > 0.2, resulting in a skeleton with 114884 1 × 1 × 1 mm3 WM voxels, corresponding to approximately two thirds of the WM voxels of the whole skeleton. TBSS then projects each subject's FA data onto the mean WM tract skeleton. The highest FA value on a line perpendicular to each point on the skeleton in each subject (which should correspond to the local tract centre value) is then projected onto the mean WM tract skeleton. Next, values of MD were mapped onto the skeleton by using the projection vectors from each subject's FA-to-skeleton transformation. The FA and MD data were analysed using the same models as for the GM and WM volume analyses described above in order to examine the linear and nonlinear (quadratic) correlation of FA (and MD) with age and the FA (and MD) comparisons between the different age subgroups. Statistical inference was carried out using TFCE thresholding in randomise (5000 permutations). Clusters were thresholded at p < 0.05, fully corrected for multiple comparisons across space. The anatomical location of the significant clusters was determined by reference to a fibre tract-based atlas of human WM anatomy (Wakana et al., 2004) integrated into FSLView. In addition to the FA and MD data used for analysis on the WM skeleton in each participant (see above), the parallel and perpendicular diffusivity data from the same voxels were also processed using the TBSS protocol.
For clusters showing significant correlation of FA (and MD) with age using TBSS, we calculated mean FA, MD, and parallel and perpendicular diffusivity values across all voxels within the significant clusters and plotted these against age to help visualize the distribution of values.
VBM-style analyses were run to assess associations of GM and WM volumes with age. Most cortical regions, with the exception of occipital pole, showed an extensive linear negative correlation of GM volume with age (Fig. 1A), especially in the left superior frontal gyrus (SFG), right middle frontal gyrus (MFG), left postcentral gyrus, right superior parietal lobule and right lateral occipital cortex (Table 1). Negative correlation between volume and age was also found in deep GM structures such as the caudate nucleus, pallidum, amygdala and hippocampus bilaterally. The correlation between volume averaged across all the GM clusters and age was r = -0.84, p < 0.001 (Fig. 1B). There were no significant linear positive or nonlinear relationships between GM volume and age.
The most significant linear negative correlation of WM volume with age were found on the right hemisphere in the anterior thalamic radiations, anterior limb of the internal capsule (ALIC), cerebral peduncle (CP), cerebellum and bilaterally in the external capsule (EC) (Fig. 2A; Table 2). The correlation between volume averaged across all these WM clusters and age was r = -0.79, p < 0.001 (Fig. 2B). No significant linear positive correlation between WM volumes and age were found. Significant nonlinear (quadratic) relationships between WM volume and age were found in the left superior longitudinal fascicle (SLF) and superior corona radiata (SCR) bilaterally (Figs. 2A and C; Table 3).
Correlations of GM and WM volumes with age were not different between males and females.
TBSS analyses of diffusion parameters were carried out to test for age-related effects on FA, MD and diffusivities. Linear negative correlations of FA with age were found in most WM regions (Fig. 3A) and were highest in the SCR bilaterally (Table 4). Region-of-interest (ROI) analysis of these clusters showed that correlation between mean FA and age was r = -0.61, p < 0.001 (Fig. 3B). There were no significant linear positive and nonlinear (quadratic) relationships between FA and age.
To test whether the linear negative correlation of FA with age was due to significant associations of parallel and/or perpendicular diffusivity, we computed the mean of these diffusivities across voxels within all significant clusters and tested for correlations with age. This analysis revealed significant correlations of perpendicular (r = 0.54, p < 0.001; Fig. 3C) but not parallel (r = 0.14, N.S.; Fig. 3D) diffusivity with age.
MD showed a linear positive correlation with age in many WM regions, with the posterior regions being less extensively affected (Fig. 4A). This correlation was highest in the SCR bilaterally, in the right SLF and inferior fronto-occipital fascicle (IFOF) (Table 5). The correlation between MD values averaged across all these WM clusters and age was r = 0.52, p < 0.001 (Fig. 4B). No significant linear negative or nonlinear relationships of MD with age were found.
Correlations of FA and MD with age were not different between males and females.
In order to identify the phases of adulthood when changes were occurring, we performed comparisons of structural measures between YA, MA and OA. However, these analysis were relatively limited by the presence of a lower number of subjects in the MA and especially OA subgroups with respect to YA subgroup.
Subgroup comparisons based on the VBM-style analysis of GM volume broadly revealed early frontal reduction followed by a later more widespread reduction. Specifically, reduction in GM volume was found in the MA compared to YA bilaterally in the frontal lobe, including the caudate nucleus and, to a lesser extent, in the temporal lobe (Fig. 5A, green; Table 6, supplemental material). A lower GM volume in the OA compared to MA was present bilaterally in the lingual gyrus, and on the right in the occipital fusiform gyrus and hippocampus (Fig. 5B, green; Table 7, supplemental material). OA showed a widespread reduction in GM volume compared to YA in several regions (Fig. 5C, green), especially in the MFG bilaterally, left SFG, right supplementary motor cortex, right precentral gyrus and left cerebellum (Table 8, supplemental material).
Subgroup comparisons of the VBM-style analysis of WM revealed that reduction in WM volume became apparent only in late adulthood. Specifically, we found no significant differences in WM volume between YA and MA whereas OA showed a reduction in WM volume compared to MA on the right hemisphere in the SLF, EC, posterior limb of the internal capsule (PLIC), fornix/stria terminalis, IFOF, bilaterally in the CP, and on the left hemisphere in the retro-lenticular part of the internal capsule (IC) and inferior longitudinal fascicle (ILF) (Fig. 5B, yellow; Table 9, supplemental material). Similar WM regions showed a significant volume reduction in OA compared to YA (Fig. 5C, yellow), with the highest differences located in the left sagittal stratum, CP bilaterally and left cerebellum (Table 10, supplemental material).
Subgroup comparisons of diffusion measures analysed using TBSS revealed that widespread FA reductions occur from middle age. Specifically, MA had lower FA than YA in many WM regions (Fig. 5A, blue), and this difference was highest in the right SCR, right body of the corpus callosum and left SLF (Table 11, supplemental material). OA had also lower FA than YA in many WM regions (Fig. 5C, blue), especially in the SCR bilaterally, right SLF and left forceps minor (Table 12, supplemental material). No significant FA differences were found between MA and OA (Fig. 5B). Interestingly, subgroup analysis suggested that MD increase becomes apparent later than FA reductions. Specifically, MD was higher in OA compared to YA in many WM regions (Fig. 6A), and this difference was highest in the right SCR, left SLF and right IFOF (Table 13, supplemental material). Compared to MA, MD in OA was higher in many WM regions (Fig. 6B), especially in the right SLF and IFOF (Table 14, supplemental material). No significant MD differences were found between YA and MA.
We scanned 66 healthy subjects aged between 23 and 81 years and found evidence for a widespread linear negative association of GM volumes and a more localised negative association of WM volumes with age. Furthermore, we found that FA, a putative marker of integrity of WM microstructure, was negatively associated with age in many fibre tracts, mainly due to a positive association of diffusivity perpendicular to the main axis of the fibre tracts. MD, which reflects overall diffusivity, showed a positive association with age in many WM regions, and this was less extensive in the occipital lobe. Each of these patterns of change, and the putative mechanisms underlying them, are discussed in detail below.
In our study most cortical and deep GM regions showed a linear negative association between volume and age. These findings are broadly in line with previous studies of similar cohorts (Good et al., 2001; Jernigan et al., 2001; Pfefferbaum et al., 1994; Raz et al., 1997; Resnick et al., 2000; Salat et al., 2004; Sowell et al., 2003; Sullivan et al., 1995, 2004; Walhovd et al., 2005), although the volume reductions we detected are even more widespread than some previous reports that have found preservation of volume in specific structures such as amygdala and hippocampus (Good et al., 2001; Sullivan et al., 1995).
There are a number of potential cellular processes that could explain these volume reductions in GM. In early adulthood, elimination of neurons and synapses (Ge et al., 2002; Webb et al., 2001) can contribute, whereas in middle and late adulthood volume reductions could be due to shrinkage of large neurons (Peters et al., 1998; Terry et al., 1987), or rarefaction in the GM microvasculature, resulting in a loss of neurons (Farkas and Luiten, 2001; Riddle et al., 2003). In addition, GM volume reductions inferred from T1-weighted images may be apparent, arising not only from genuine decreases in neuronal volume but also from changes in myelination, affecting the intensity of the MR signal (Sowell et al., 2003). This may be a plausible mechanism in early adulthood because of ongoing processes of myelination (Yakovlev and Lecours, 1967) but is less likely to play a role in later adulthood. This last hypothesis may explain why different ageing trajectories have been previously found in different cortical areas, appearing linear in visual, auditory and limbic cortices, which complete myelination early in life, and nonlinear or more complex in associative frontal and parietal cortices and posterior temporal cortex, which continue myelination into adulthood (Sowell et al., 2003).
The total WM volume follows a nonlinear inverted "U-shaped" relationship with age, slightly increasing during the early adulthood, consistent with the notion of an ongoing maturation of the WM beyond adolescence, and then reaching the peak in the fourth decade (Ge et al., 2002; Sowell et al., 2003; Walhovd et al., 2005).
Using a VBM-style analysis, we found linear negative association of WM volume with age especially in the external capsule bilaterally, and in the right anterior limb of the internal capsule, anterior thalamic radiations, cerebral peduncle and cerebellum. Significant nonlinear (quadratic) relationships between WM volume and age were present in the superior corona radiata bilaterally and in the left superior longitudinal fascicle. These findings seem to contrast with those of a recent study on 84 normal subjects aged 13-70 years (Pagani et al., 2008), where linear negative associations between volume an age were found in the fronto-parietal lobes (corona radiata, anterior cingulum, fornix) and left cerebellar peduncle and nonlinear relationships with age in the genu of the corpus callosum and in the right deep temporal association fibres. The presence of different areas where WM volume is related to age, found by the two studies, may be due to the fact that Pagani et al. (2008) included younger subjects and used a DTI-based technique, and not VBM, to assess white matter fibre volumes.
Our findings suggest that both heavily myelinated fibres (e.g., corticospinal tracts, located in the posterior limb of the internal capsule) and thinly myelinated fibres (e.g., association fibres of the frontal lobe) are affected in the same way by the pathogenic mechanisms underlying the ageing process. The involvement of the motor system during ageing is confirmed in the current study by the fact that volume in precentral gyrus, where that system is expected to originate, showed a significant inverse correlation with age and by the findings of previous histological studies, where an age-related decrease in the number of pyramidal fibres in the spinal cord and a thinning of precentral gyrus were reported (Salat et al., 2004; Terao et al., 1994).
WM atrophy could be a result of the ageing process per se or a consequence of the effects of WM lesions, which may be present in the neurologically asymptomatic elderly population (Enzinger et al., 2005; Pagani et al., 2008; Rovaris et al., 2003). However, none of our subjects had the presence of WM lesions and, further, a previous study found no overlap between regions showing age-related atrophy of WM fibres and the presence of WM lesions (Pagani et al., 2008).
Overall, we demonstrated here that the loss of WM integrity over adulthood and ageing might be explained in the corticospinal tract by WM atrophy.
In addition to the VBM-style analysis of WM volume described above, we also tested for age-related change in DTI metrics of WM microstructure. We found widespread linear negative associations of FA with age, consistent with previous reports (Ardekani et al., 2007; Head et al., 2004; Madden et al., 2004; O'Sullivan et al., 2001; Pfefferbaum and Sullivan, 2003; Salat et al., 2005a, 2010).
When comparing the different age subgroups, both middle-aged (41-59 years) and older (60-81 years) adults showed a significant widespread FA decrease compared to young adults (23-40 years) whereas middle-aged and older adults were not significantly different from each other, suggesting that the loss of directionality in WM fibres becomes apparent during the transition from early to middle adulthood. Again, this is in line with the study by Salat et al. (Salat et al., 2005a), where FA differences between young adults (21-37 years) and older adults (65-76 years) were apparent by middle adulthood (42-59 years). In the current study, the presence of widespread FA reductions in the transition from young to middle adulthood was demonstrated earlier than the volume reductions shown by our WM VBM-style analysis and earlier than the existing volumetric literature on WM (Bartzokis et al., 2001; Ge et al., 2002; Sowell et al., 2003; Walhovd et al., 2005). This regional decline in FA with early ageing occurs in the absence of significant regional increase in FA elsewhere, suggesting that middle adulthood may be the time when the transition from development to ageing in white matter fibre coherence takes place.
The findings of our study challenge the idea that early myelinating posterior regions are less susceptible to age-related change than late myelinating regions of frontal lobe white matter. Although previous DTI studies have provided some support for this idea, i.e. greater age-related FA decline in frontal compared to posterior WM regions (Abe et al., 2002; Ota et al., 2006; Pfefferbaum et al., 2005; Salat et al., 2005a,b; Sullivan et al., 2006), our results are more closely in line with studies where a decrease in FA was found not only in regions of the frontal lobe but also in more posterior regions such as the splenium of the corpus callosum and posterior limb of the internal capsule (Ardekani et al., 2007; Furutani et al., 2005; Salat et al., 2005a).
Our results also demonstrate that the two major tracts connecting limbic structures in Papez circuit (i.e., fornix and cingulum) are both affected by ageing. The involvement of the fornix in our cohort of subjects is also confirmed by the fact that volume of hippocampus, a GM structure connected by the fornix, showed a significant inverse correlation with age. However, these results appear to conflict with a recent study in subjects aged 18 to 88 years, where cingulum but not fornix appeared resistant to ageing (Stadlbauer et al., 2008).
In our study, MD showed a spatial pattern of associations with age broadly similar to FA, although it seemed that posterior regions of the WM were less extensively affected. The comparison across different age subgroups showed that, in contrast to FA changes, changes in WM MD appear as a late ageing phenomenon, consistent with a previous study which used slightly different age ranges for the two groups (Ardekani et al., 2007).
The assessment of parallel and perpendicular diffusivity may enhance the specificity of DTI findings and shed light on the mechanisms underlying FA changes. Changes in parallel and perpendicular diffusivity have been related to axon and myelin damage, respectively, in mouse models of multiple sclerosis (Budde et al., 2007a,b; Song et al., 2005; Sun et al., 2007; Wu et al., 2007), dysmyelination (Song et al., 2002) and retinal ischemia in the optic nerve (Song et al., 2003). Moreover, perpendicular diffusivity, together with FA and MD, was shown to be a robust predictor of myelin content in post-mortem human brain, prior to and after fixation (Schmierer et al., 2008). However, the degree to which these relationships hold in the healthy living human brain remains to be determined. Nevertheless, interrogating how the different diffusivities contribute to observed FA changes provides complementary information. In the current study, we found that negative correlation of FA with age was mainly driven by positive correlation of perpendicular diffusivity, whereas parallel diffusivity only showed a slight non-significant positive correlation with age. These findings are in line with other recent studies testing the tensor diffusivities during ageing (Bastin et al., 2009; Bhagat and Beaulieu, 2004; Ota et al., 2006; Salat et al., 2010; Stadlbauer et al., 2008; Sullivan et al., 2010; Vernooij et al., 2008) and may be explained by the presence of degenerative changes in the myelin sheaths or, alternatively, of a reduced fibre organisation or "packing" (i.e., a decrease in the number of axons) within WM tracts.
In our study, FA changes overlap with regions showing evidence for WM atrophy (i.e., reductions in WM volume using VBM-style analysis) in the forceps minor, internal and external capsules, cerebral peduncle and temporal association fibers, consistent with previous reports showing similar changes in FA and VBM measures of WM (Vernooij et al., 2008). At the level of the superior corona radiata, however, out data suggest that this relationship seems to be present only after 50 years of age. Further, in all others areas loss of WM microstructure was detected in the absence of significant WM changes on VBM-style analysis. This suggests that DTI can provide more sensitive information on ageing-related WM degeneration compared to volume metrics.
Our study benefited from some methodological advances compared to previous DTI studies investigating ageing-related FA changes. First, data were acquired using 60 diffusion directions, thus providing increased power and higher angular resolution compared to some previous investigations. Second, we used a technique for sensitive and robust voxelwise analysis of DTI data (Smith et al., 2006) as well as an improved approach to statistical thresholding which enhances all cluster-like structures present in an image avoiding the need for the arbitrary initial cluster-forming threshold (Smith and Nichols, 2009).
In studies on the ageing brain, the quality of image registration is an important issue, especially as it applies to small structures such as the hippocampus. Indeed, an age-related volume decline of such structures may represent an artifact of distorted shape from adjacent, expanding fluid-filled spaces rather than a real atrophy process. However, as registration was accurately checked, we do not believe that results of this study are due to misregistration.
However, there are some limitations to this study. First, we had fewer subjects in the older age groups, and this might have underpowered the subgroup comparison analyses. Second, the study has a cross-sectional design and therefore, because it contains different cohort of subjects in different age groups, it may be less sensitive to brain changes across the lifespan than a longitudinal study. Third, we recognise that age clustering in this study is arbitrary. However, as we mention in the Methods section, grouping selection was broadly in line with previous studies. In addition, we deliberately included complementary analyses (i.e., testing for correlations across the whole age range) that were not dependent on this grouping. Finally, after performing residual analysis of all plotted measures in the different regression analyses, we found no clear evidence for heteroscedasticity and no outliers in the VBM or FA analyses and only one outlier in the MD analysis (data not shown). However, it should be noted that regression analysis is relatively robust to homoscedasticity and small-to-moderate violations of homoscedasticity have only minor impact on regression estimates (Fox, 2005).
In conclusion, we assessed a number of measures of brain structure to characterise the spatial and temporal pattern of changes that occur in both GM and WM with normal ageing. Reductions in GM volume appear in middle age and then become more widespread into older adulthood. Widespread age-related decline in WM microstructure occurs earlier and can be detected more sensitively using DTI-based measures of microstructure than using markers of WM volume derived from conventional T1-weighted imaging. The observed patterns and dynamics of normal age-related changes may have important implications for future studies on chronic neurological conditions that show an impact of age on disease onset, course and progression, such as Alzheimer's disease, Parkinson's disease and multiple sclerosis (Baquer et al., 2009; Reeve et al., 2008; Trojano et al., 2002). The application of these novel MRI techniques may be useful for furthering our understanding of pathologic substrates underlying such neurological conditions, for charting their evolution and monitoring response to treatment. Finally, the study of age-related brain changes may potentially benefit from the use of high field scanner MRI acquisition, which provides increased signal-to-noise ratio and so opens possibilities for greater spatial resolution, although issues related to field inhomogeneities and increased chemical shift (Pagani et al., 2007) deserve further investigation.
HJB is grateful for financial support from the Wellcome Trust, Stroke Association and NIHR Biomedical Research Centre, Oxford. VT is grateful to the Italian MS Society (Fondazione Italiana Sclerosi Multipla, FISM) and British MS Society for their support.
Appendix ASupplementary data associated with this article can be found, in the online version, at doi:10.1016/j.neuroimage.2010.03.004.
Local maxima within each significant cluster showing significant (corrected p < 0.05) lower grey matter volume in the middle adult subgroup compared to the young adult subgroup. The grey matter clusters are ordered by decreasing Y coordinates of their local maxima.
Local maxima within each significant cluster showing significant (corrected p < 0.05) lower grey matter volume in the old adult subgroup compared to the middle adult subgroup. The grey matter clusters are ordered by decreasing Y coordinates of their local maxima.
Local maxima within each significant cluster showing significant (corrected p < 0.05) lower grey matter volume in the old adult subgroup compared to the young adult subgroup. The grey matter clusters are ordered by decreasing Y coordinates of their local maxima.
Local maxima within each significant cluster showing significant (corrected p < 0.05) lower white matter volume in the old adult subgroup compared to the middle adult subgroup. The white matter clusters are ordered by decreasing Z coordinates of their local maxima.
Local maxima within each significant cluster showing significant (corrected p < 0.05) lower white matter volume in the old adult subgroup compared to the young adult subgroup. The white matter clusters are ordered by decreasing Z coordinates of their local maxima.
Local maxima within each significant cluster showing significant (corrected p < 0.05) lower white matter FA in the middle adult subgroup compared to the young adult subgroup. The white matter clusters are ordered by decreasing Z coordinates of their local maxima.
Local maxima within each significant cluster showing significant (corrected p < 0.05) lower white matter FA in the old adult subgroup compared to the young adult subgroup. The white matter clusters are ordered by decreasing Z coordinates of their local maxima.
Local maxima within each significant cluster showing significant (corrected p < 0.05) higher white matter MD in the old adult subgroup compared to the young adult subgroup. The white matter clusters are ordered by decreasing Z coordinates of their local maxima.
Local maxima within each significant cluster showing significant (corrected p < 0.05) higher white matter MD in the old adult subgroup compared to the middle adult subgroup. The white matter clusters are ordered by decreasing Z coordinates of their local maxima
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Notify Fans of Concert Dates Through Google Search
Photo of the author, Jennifer Beese by Jennifer Beese on February 24, 2012
This feature can help create more awareness not only for bands, but for music venues as well. If you have a website listing upcoming events and would like them to appear in search, you can add rich snippets markup to your site.
Currently this is only available to people searching on google.com in English. The company plans to launch the feature in more countries in the future.
[Via: The Next Web, Image credit: Ibrahim Iujaz]
Jennifer Beese: Jennifer Beese has worked as a community manager and social media strategist. When she's not writing, you can find her studying anatomy and physiology—she literally has a skeleton in her closet—or under the stars with her telescope.

subset: commoncrawl


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Get an overview of this hotel3-star Lyon hotel in 6th Arrondissement, near Tete d'Or Park
Popular property highlights
Located in 6th Arrondissement, this hotel is within 1 mi (2 km) of Oxygen Tower, Tete d'Or Park, and Lyon Opera. Lyon City Hall and Terreaux Square are also within 1 mi (2 km).
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A 24-hour front desk, free newspapers, and tour/ticket assistance are available at this smoke-free hotel. WiFi in public areas is free.
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All rooms are soundproofed and offer free WiFi and free bottled water. For a bit of entertainment, flat-screen TVs come with digital channels, and guests will also find coffee makers and hair dryers.Information missing or incorrect? Tell us!Opens in a new window
Timhotel Lyon La Part Dieu
Hotel Amenities
Hotel Amenities
Timhotel Lyon La Part Dieu features a terrace, tour/ticket assistance, and complimentary newspapers in the lobby. Wireless Internet access is complimentary. A total renovation of this property was completed in November 2014.
Timhotel Lyon La Part Dieu is a smoke-free property.
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- Tours/ticket assistance
- Free WiFi
- Terrace
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- Smoke-free property
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Available in all rooms: Free WiFi
Available in some public areas: Free WiFi
Room Amenities
- Soundproofed rooms
- Free bottled water
- Coffee/tea maker
- Daily housekeeping
- Private bathroom
- Free toiletries
- Hair dryer
- Shower only
- Desk
- Iron/ironing board (on request)
- Digital TV service
- Flat-panel TV
- Free WiFi
Where to Eat
Buffet breakfasts are available for a surcharge.
If you have requests for specific accessibility needs, please note them at check-out when you book your room.
- In-room accessibility
Hotel Policies
Minimum check-in age is 18
Check-out time is noon
Payment types
Children and extra beds
- Children are welcome.
- Kids stay free! One child 12 years old or younger stays free when using existing bedding.
- Rollaway/extra beds are not available.
- Cribs (infant beds) are not available.
- Pets allowed for an extra charge of EUR 10 per pet, per night (maximum EUR 10 per stay)
- 1 per room
You need to know
Extra-person charges may apply and vary depending on property policy.
Government-issued photo identification and a credit card or cash deposit are required at check-in for incidental charges.
Special requests are subject to availability upon check-in and may incur additional charges. Special requests cannot be guaranteed.
- No onsite parking is available.
24-hour check-in
No rollaway/extra beds available
No cribs (infant beds) available
This hotel will place a pre-authorization on credit cards for bookings of 3 nights or more. For more details, please contact the office using the information on the reservation confirmation received after booking.
- A tax is imposed by the city: EUR 1.10 per person, per night. This tax does not apply to children under 13 years of age.
Optional extras
- Fee for buffet breakfast: EUR 9.0 per person (approximately)
- Pet fee: EUR 10 per pet, per night (maximum EUR 10 per stay)
Hotel Name
- Timhotel Lyon
- Timhotel Lyon Part Dieu
- Timhotel Part Dieu
- Timhotel Part Dieu Hotel
- Timhotel Part Dieu Hotel Lyon
- Britania Hotel Lyon
- Timhotel Lyon Part Dieu Hotel
We should mention
One child 12 years old or younger stays free when occupying the parent or guardian's room, using existing bedding.
National Rating
This property has received its official star rating from the French Tourism Development Agency, ATOUT France.


text:
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Today, my dad yet again uttered the words "well, that escalated quickly," while watching the news. He uses this godforsaken meme multiple times a day. I lost my shit and told him to just shut up already. He raised an eyebrow and said, "well, that escalated quickly." FML
Today, it was raining heavily so I wore my black poncho as I walked to work. On the way there I noticed an old and seemingly homeless man following me. I turned around to confront him. He picked up a stick and screamed "Expecto Patronum!" Apparently I look like a dementor. FML
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text:
We're upping the ante as Carlos & Killian
clash once again bringing the points
up to 300 for this Infinity Battle Report!
We're upping the ante as Carlos & Killian
Once you've played a few games with Infinity's Operation Red Veil you'll need to look at expanding your forces and we have you covered!
Now you've seen the Unboxing for Red Veil you can come and check out how you assemble the terrain from the set crafting your own Neon Lotus Space Station.
It's time for a Battle Report showdown as Killian & Carlos battle it out with Yu Jing and Haqqislam forces using Operation Red Veil!
Infinity: Operation Red Veil Unboxing384 days ago 478
Join us for the first video of Operation: Red Veil Week where we'll be taking you through the new Starter Set for Infinity by Corvus Belli…
Get your head around how Modifiers work within the world of Infinity in a How To Play video from Corvus Belli…
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If you're new to Infinity this video will guide you through the basic game concepts and how to play. Next step; getting stuck into the action yourself!
We sit down to discuss the Design Choices that went into creating the new Operation Red Veil Box for Infinity…
Infinity – Operation: Red Veil Week Coming Monday!389 days ago 36
Join us for Operation: Red Veil Week for the Infinity Miniatures Game starting next week on Monday 4th July!


text:
OBR Daily Blogs
Archive for September, 2010
Did Browns approach Eagles about Kolb?: One day after he loses his starting quarterback job, Kevin Kolb is the sub… http://bit.ly/9MKgeG
Peyton Hillis Lovin' Life, The OBR…
Barry McBride on September 22nd, 2010 AT 9:27 PM
OBR Ambassador Joe Caggiano took these photos at Panini's Cams Corner at a recent event there.
See how easily Peyton can get into that Smart Car? That's what we've been telling you about on the radio.
(Subscriber) Xs & Os: A Rapid Recovery: Doug Farrar explains how a veteran quarterback can go from looking so bad … http://bit.ly/cOZAZ4
Cribbs Unable To Get Going: In the first two games, Tampa Bay and Kansas City have kicked away from Cribbs on spec… http://bit.ly/bn70GA
Browns-Ravens Injury Report, Sept. 22
Don Delco on September 22nd, 2010 AT 5:22 PM
Jake Delhomme, QB (ankle)
Jerome Harrison, RB (thigh)
Shawn Lauvao, OL (ankle)
Evan Moore, TE (head)
Derrick Roberson, DB (hip)
Brian Robiskie, WR (hamstring)
Shaun Rogers, DL (ankle, hip)
Robaire Smith, DL (ankle)
D'Qwell Jackson, LB (chest)
Matt Roth, LB (foot)
Floyd Womack, OL (knee)
Eric Steinbach, OL (thigh)
Joe Thomas, OL (elbow)
Tavares Gooden, LB (shoulder)
Donte Stallworth, WR (foot)
Jared Gaither, OL (back)
Derrick Mason, WR (knee)
Le'Ron McClain, FB (shoulder)
Dannell Ellerbe, LB (knee)
Todd Heap, TE (shoulder)
Jarrett Johnson, LB (back)
Jameel McClain, LB (knee)
Haloti Ngata, DT (back)
Ray Rice, RB (ankle)
Terrell Suggs, LB (ankle)
Browns player quotes, Sept. 22
Don Delco on September 22nd, 2010 AT 4:02 PM
Below are player quotes obtained by the Browns' PR staff on Sept. 22.
WR Joshua Cribbs
(On the receivers needing to give the quarterback more help on sideline routes)- "The quarterbacks throw the ball and it's our job to catch it. If the ball is going toward the sideline and we have to go get it. It's our job to stay in bounds. We will do a better job of staying inbounds and the receivers are doing everything they can to stay inbounds. They want to catch the ball, they want to be inbounds. It's just a point of practicing it, keeping our feet in and making that adjustment."
(On if he agrees with the coaches saying they want to run more of the Wildcat offense)- "I'd rather just leave it at what they said. I want to leave it all out there on the line. Each and every game, I want to play like it's our last, then we will think of a whole other scheme for the next team. I want to come out and just call every play we have that can give us that win because we need wins. The next game, if they have got it beat, then we will come out with a whole different type of package or something and leave it all on the table. That's the kind of plays that I want to see. They're coaches, I'm going to let them coach. I'm going to just play."
(On if there is still time to turn the season around)- "Of course, we have got 14 games left, so there's a lot of football left. You saw how our season went last year, even at the end of that season, we went on a roll. We are trying to start something before that time, before we even get a lot of losses, we want to start winning now. Right now."
LB Scott Fujita
(On what he would expect from Baltimore's offense after they threw four interceptions last game)- "I think in general, you would expect them to try to get back to the run and keep things basic for him, but you never know in this league. As soon as you think you have got a team pegged, they come out and do something different and surprise you. With those receivers, I don't see them just trying to pound the ball. They have got to try and get those guys involved in the game plan."
LB D'Qwell Jackson
(On how long it would take him to get back into game shape)- "Game shape is not a problem. I've been making sure I've been keeping my conditioning up. Like anything else, once those bullets are flying on Sunday, it's a different type of test. Today, I'm going to go out here and try to work on everything I can, taking on a block, pass rush and try to work everything that I would to try and simulate a real game. Today will definitely be a good test for me to see if my body holds up so I can move forward to tomorrow."
(On if his first game back is against Baltimore)- "They play power ball. They have a lot of good talent over there from receivers to Ray Rice, all across the board. It will definitely be a power game. If I come back it will be full go and I'm up for the challenge."
QB Seneca Wallace
(On if he has ever played against Baltimore)- "No, I haven't. This is my first time playing against them, but I know that they are a very physical defense. They create a lot of turnovers, they have always been that way. A very talented defense."
(On what he will do to prepare against one of the best defenses in the league)- "Same thing I've been doing. You can't press and try to do more because you're playing against a better defense. You have just got to continue to keep playing football and continue to keep doing what you've been doing."
(On if he has ever previously studied Baltimore)- "Yes, we played Baltimore a couple of times when I was in Seattle. That's why I said, I know they are a very physical defense. They do a lot on third down to try and create a lot of turnovers and disguise some things. That's the only thing I can say about them. Everybody knows they are a good defense, a great defense. We have just got to control what we can on the offensive side."
(On if he moved around in the pocket as much as he normally does versus Kansas City)- "I don't know. It depends on how you view that, how you view how much I move around in the pocket. Not much though."
(On if he moves around in the pocket to escape pressure or if it is by design)- "To escape sometimes."
(On if there are any designed rollout plays)- "We do have some. We have a few that we have in our offense, but we didn't dial them up as much last week. We will see what happens this week."
(On if he is more comfortable rolling out of the pocket)- "Either way, it doesn't matter. Rolling out or staying in the pocket, whatever I have to do to complete the ball, I'm going to do that."
(On if there are some defenses that the Wildcat is better against than others)- "Yes, probably so. Teams that have seen the Wildcat and aggressive defenses like this one here, it can be at a disadvantage sometimes. You have got to pick and choose when you want to use it and when to utilize it. (Joshua) Cribbs is a great athlete, so he is going to make it happen, whatever defense we are against."
(On if the Wildcat won't work as well against an aggressive defense like Baltimore's)- "No, it will work well against an aggressive defense, but you have just got to pick and choose when you want to call those plays."
(On if it is dangerous running the Wildcat with him in the open field when the team is already down a quarterback)- "It could be dangerous, but I have just got to be smart about it make sure I stay away from other players and stay healthy after the play."
(On if he relies on his offensive line having experience against Baltimore's stunts and blitzes)- "Yes, but I have still got to be in tune with the offensive line. Making sure I know where my hots are going to be, making sure I know where the Mike point is going to be, but it's a good thing that the offensive line played against them twice last year. They've seen the fronts, they've seen the defense, they know the defense, so that always helps."
(On if he is feeling better going in to potentially his second start)- "A lot better. Just getting another week under your belt, you kind of get into the groove of things and how a regular work week is. It helps a lot. It helps a lot going into your second week as a starter."
(On if playing better is as simple as correcting the turnovers and penalties)- "Yes. We are a play here and there away from being undefeated, but like we said, we shot ourselves in the foot. We had some turnovers and they came back and hurt us. We have just got to make sure we protect the ball and do all of the things right. That's what it comes down to."
(On if they can take fewer chances because Baltimore thrives on turnovers more than other teams do)- "No, you still have to be aggressive, but you have got to be smart at the same time. You can't be complacent and not try to go up top and take a shot on them. Their defense sometimes can give up big plays, so we have still got to be aggressive and do what we do on offense."
(On if the offense feels like it is missing opportunities to get wins because of how well the defense is playing)- "Yes, the defense has been playing very well for us. Offensively, like I said, we did some things that kind of hurt us. It puts our defense in a bad situation and so we have got to make sure that offensively, we don't put them in that situation."
(On if anything stood out from the second half Sunday as to why the offense had trouble moving the ball)- "Not really. We just had a few little mistakes and penalties and things like that that put us in tough spots. Any team in the NFL, if you get third and long or third and 8 plus, it's hard to convert that."
(On if the offense could used the middle of the field more)- "Probably so, it was just what the defense was giving us. We missed a few of them and it's tough. You have just got to keep playing football."
(On if he has the mentality that he is going to start Sunday)- "I still have got to keep doing what I've been doing. I have got to prepare and get the team ready for the game on Sunday."
Rumors emerge of the Browns and Kolb
Barry McBride on September 22nd, 2010 AT 3:36 PM
Philadelphia radio station WIP relayed earlier that the Cleveland Browns have inquired about quarterback Kevin Kolb, the Eagles QB who recently took a back seat to Michael Vick.
My experience with trade rumors started on radio stations hasn't been entirely positive, but the Browns interest in Kolb is pretty well documented. The team inquired about his availability during the off-season, as the Eagles sorted through their quarterback situation. The Heckert connection is pretty obvious, so it's not far-fetched to think that a call was placed.
Why the conversation was leaked to the radio station, assuming it's accurate, is another question, and might be an indication that the team is trying to hype interest in Kolb. the existence of the phone call isn't in and of itself significant – teams have these conversations all the time, and the Browns need to find a long-term answer at QB.
I wouldn't expect much to come out of this in the short-term, as in-season trades are relatively rare, and Kolb would bring with him demands for a fairly high draft pick in return. He wouldn't turn around the Browns season, so there's not a strong reason for the team to move hastily. It is, however, something we will want to keep a sharp eye on prior to the draft, as the Browns will have an interesting set of potential selections to tempt them.
@SheriffKevin Browns called about Kolb during the off-season as well. In-season trades are infrequent.
Mangini Press Conference Transcript, Sept. 22
Don Delco on September 22nd, 2010 AT 3:16 PM
Below is the transcript from Eric Mangini's Wednesday press conference, as provided by the Browns' PR staff:
(Opening statement)- "Good morning everybody, welcome back. A couple notes on practice today, guys that won't be practicing today are Jake (Delhomme), Shaun Rogers, Shawn Lauvao, Evan Moore and Robaire Smith. Hopefully, as the week goes on we'll get all those guys back, but each one is sort of at a different phase and we'll just take it as it goes. D'Qwell (Jackson) will be back out there today so that's good news. We'll see how well he responds to increasing the amount of repetitions he has and increasing the amount of opportunities he has. I like the things he did on Friday, this is just the next step in his progression.
"In terms of prepping for the Ravens it is going to be challenging. This is their home opener. It's always loud when you play there. My experience here, we played there one time in New York, very, very loud atmosphere. I expect it to be that much more excitement being the home opener so that will be something we'll have to deal with. Looking at their team, John's (Harbaugh) done a really nice job, all three phases are talented, all three phases have played well. Defensively, they can turn the ball over which they have done historically and they've been very, very successful when they've won the turnover ratio. I think they're 68-4 when they're +1 or better. That's a pretty impressive number. They've got a lot of really talented guys that play hard. I know we talk about Cal Ripken and Brett Favre in terms of longevity, but look at a guy like Ray Lewis playing 15 years at the position that he plays with the intensity level that he plays at. It's impressive. I know I've shared this story before, but I was there the year that we drafted him and his first OTAs and his presence it was obvious. He took control of that defense right away, he took control of that situation right away and he hasn't let go since. It's amazing that you can play as violent as a position he plays and play it at that level. What he does too is he is a little bit of a force multiplier because he gets the people around him to play better. Look at their numbers, they've done great things. They're number one on third down, they can pressure the quarterback with four when they bring full pressures. Each one of their defensive linemen sort of brings a different package as to how they rush the quarterback. They've been good in the running game, so a lot of challenges there."
"Offensively, I think it is a really talented group. Joe Flacco I know his numbers aren't what they were at the end of last season, but he's got a tremendous arm. He can make any throw, he's very accurate and he can hurt you at any point short or down the field. Ray Rice runs the ball, I think, very well. The other thing Ray Rice does, similar to Jamaal Charles, is catch a lot of balls. I think 78 balls last season coming out of the back field. Then they complement him with Willis McGahee, the receiver group (Anquan) Boldin, (Derrick) Mason, T.J. Houshmandzadeh, Todd Heap, all playmakers. There are quite a few challenges there as well.
"We move to special teams, I'm sure it's going to be probably about the same thing. John's (Harbaugh) influence there is apparent, his background. It's a physical group like the offense and defense, they're pretty close to the top of the league in most statistical categories. I think one of the things we need to continue to get better at is the return game. There have been different things that people have been doing to get the ball away from Josh (Cribbs). When that does happen, the guys who do get the ball need to make those pop-kicks count as much as we possibly can. In their return game, it's physical as well. They get up the field quickly and create field position that way."
(On if Jake Delhomme's will play Sunday at Baltimore)- "I don't really have a percentage for you but it gets better each day, which is a good thing. He's doing everything he possibly can. He's here first thing in the morning, here late at night. I feel really comfortable with his ability to take the information with or without reps and be able to execute it. I'm optimistic, I think we are obviously further ahead than where we were. I was optimistic last week, we'll just have to see how it goes."
(On if it is tough for a quarterback to step in and play against Baltimore when they have not faced them too many times)- "I think even the guys that have been in the division have a tough time with them. I think that one of the difficulties that they're able to create is, they can generate pressure from three, four and they have a pressure package as well. It's not just a function of okay if we handle their pressures and pick them up and get a hat for hat then we'll be able to do the things we want to do. It's being able to handle their pressures but it's also being able to handle the front as well when it is three or four. That's one component of it from a coverage perspective. There will be some coverage variation but that's pretty common with every time that we face. I'm not sure the last time Seneca (Wallace) or Jake (Delhomme) has faced them."
(On if Anquan Boldin has made an impact on what the Baltimore offense wants to do)- "He's an incredibly talented guy. He has great hands, runs good routes, he's tough. He had the game there in New York where he had a head to head collision and he was out for three weeks and he came back. I was talking to Keith Gilbertson and he mentioned this that he came back three weeks later and had double digit catches against them. That's the kind of toughness this guy has, so that does present a challenge. I think Todd Heap's playing really well. Derrick Mason has been so consistent whether it's been in Baltimore or Tennessee. He's a veteran guy that understands how to get open, runs really sharp routes, mix in T.J. Houshmandzadeh and the backs out of the backfield because they can press you vertically, check it down to Ray Rice and he is pretty dangerous with the ball as well."
(On if Seneca Wallace is being kept in the pocket purposely)- "No, he had the one scramble for a first down when we got the holding penalty so that was one play he made with his feet. He had another one where he scrambled, it was after we had gotten the turn over right before the field goal and hit (Brian) Robiskie on the sideline. That was a scramble play that he made happen. There were a couple other ones that maybe not the dramatic out of the pocket type things but where he bought some time and gave us a chance to make some plays. I don't think he's gone into the regular season with a different approach as to how he's going to play the game. I don't see a big shift in his approach that way."
(On if Seneca Wallace's needs to move to create passing lanes because of his height)- "No, because he's been an accurate passer and the height of the offensive linemen here and in Seattle are pretty comparable."
(On Wallace being more accurate when he moves)- "Not always though. Even when he's in the pocket, he's been accurate because he's decisive with throwing the ball and he's accurate as a passer. I think it's another component as to what he can do and there are a lot of guys like that. Joe Flacco moves around a lot in the pocket as well and generates some plays. We see it with Ben (Roethlisberger), those are two bigger guys, Carson Palmer. It's more that sense of where the rush is, where the pressure points are and then being able to slide away from it. Tom Brady isn't a big scrambler but what he does well is he just slides away from the pressure to buy enough time to keep the play going. It may look a little bit more dramatic because of how wide Seneca goes sometimes but I think a lot of the quarterbacks who can effectively generate some time usually create some plays down the field."
(On if he feels confident in the improvement of the secondary)- "Yes, I've been happy with some of the things that we've done in the secondary. Sheldon Brown's interception, I showed it to the group not just because it was an interception, but the way that he played the ball. That was a teaching play because he moved into the receiver as he was looking back, he didn't give the receiver any space to push off. He high pointed the ball. He created that play. I'm really happy to see that. Where I've been most happy with the group is they're working well together. They spend a lot of time watching tape as a group. You may think that should happen. That doesn't always happen, one guy wants to watch it at his house, another wants to do this, their kind of like the offensive line. If there's any uncertainty, with the offensive line it ends up being a sack, secondary usually ends up being a big play or touchdown. I like the way they've consistently worked together. There are new guys, there are young guys and that's been important and I think that's really helped us as a group. But that being said, they're going to be tested and each one of those guys can test them. We face good receivers every week, but it's a combination of you got the tight end, you got the three wide receivers, you got the back who is very effective out of the backfield. Usually one of those positions doesn't have 78 catches, one of those positions can be spit out as a wide receiver at 250 lbs and go up and catch vertical balls. The quarterback, I don't know if you guys saw the play against the Jets where he threw a comeback to Mason, it was a rope. The guy turned around and it was in his hands. It was a great catch, but talk about timing. There is a pretty small margin for error there."
(On if Evan Moore sustained a concussion last Sunday)- "Yes. The process now is he has to come back and be symptom-free and then he gets tested by our doctors and gets tested by an independent doctor. There's a layer of things that have to happen for him to come back and participate. I think it's a good system. I think the league has worked hard on it, teams have worked hard on it to make sure that guys are coming back at the right time. It's important to do."
(On if he will be more cautious about sending a player back in the game that just had a head collision)- "I don't think we lacked caution Mary Kay (Cabot). I don't think it was a function of, 'Forget about what happened, send him back in.' We have the trainer and the doctor on the sideline, that's never a coaching decision. Everybody is doing the best they can to make sure the players' safety is first. I know how good Joe (Sheehan) is and how good our doctors are and we are going to work each game to make sure that we don't put a guy in a spot that he shouldn't be in. It's important to us not to do that."
(On if players with concussions come in to the facility each day or stay at home)- "Really again, it goes to the medical staff. They have a process that we go through. Sometimes they may stay home and rest and then come back the next day. There's constant communication with anybody who's injured or rehabbing or along those lines. There's protocol in place for each different type of injury. That's really, again, handled by them and I count on them."
(On if Moore is in Berea or at home)- "Evan is here today. He's made tremendous strides, it's just you have to go through the steps before you're cleared to play."
(On if it is possible for Moore to play Sunday)- "Yes, I think there's a possibility."
(On if James Davis could get more reps at running back on Sunday)- "I'm not opposed to it Tony (Grossi) at all, it just depends on how the game is going. One of the important things is generating first downs, generating the opportunities, having more plays to do things with. When you get those plays, you can add variety, you can do some more things. He's worked hard, he's done a pretty good job on special teams, which is what his primary role has been over the last couple of weeks, but I don't lack any confidence in him going in and doing well as a running back."
(On if Davis is lacking anything in practice to earn carries at running back)- "No, no, that's not what I meant Jeff (Schudel). What I'm saying is each week, you look at the guys. If the guy is having a stand out week in practice, you just view it as earning opportunities in the game. That's really how Evan Moore got his first chance is he stood out in practice, so he got opportunities in the game. You're always looking for that. It happened quite a bit last year. Marcus Benard, Titus Brown is back now with us. Did you guys get that update on Kaluka (Maiava) being on IR and Titus coming back? Titus is another guy that worked hard. To me, it's not something they're lacking. When you are in one of those spots, you have to create those opportunities for yourself. You'll get them, we are looking for them. You'll get them and when you get them, if you do well, you get some more. (Brian) Schaefering, Marcus, Evan, there are quite a few guys like that."
(On Bernie Kosar saying that the receivers are not helping the quarterbacks enough on sideline routes)- "I really respect Bernie, but from my perspective, I think the receivers work hard at what they do. I think there were opportunities that we had that we could have capitalized on. I like to think that the next time we have that opportunity, we will capitalize on them. I think Brian Robiskie is a good sort of indicator of that where the first game, he had two where he was close to the sideline and we couldn't quite make the play. Then we come back this game and he had that better awareness on the sideline and he made the play. That was one of Seneca's (Wallace) scramble plays there towards the end of the half and he made that play. It is a young group, they're going to keep developing. There's going to be some things that you're in year two, you're going to make some mistakes and want some plays back, but they will work at it and they will get it corrected. I believe that next time we have that chance, they will do a better job."
(On if Shaun Rogers is being held out of practice for the same reasons as last week)- "Yes, it's the same thing. We will just gauge it."
(On if Rogers is not able to get in game shape because of limited reps in practice and camp)- "I didn't feel like he was out of shape at all in this past game. You want guys to practice every single day, sometimes it's just not realistic. Robaire (Smith) can't go today and sometimes they may practice, but we may limit their plays and you're balancing. Guys at different ages at different levels that tneed to get prepared. You'd love every guy to be able to take every rep each day, but it's just not realistic, especially over a 16 week schedule, to do that. You have to balance it and prepare accordingly."
(On if Rogers got as many game reps as he thought he would last Sunday)- "He was right about at that same range as last week. That was kind of the thought process here early. Hopefully we can bump it up a little bit each week, but you have just got to adjust to it."
(On if there is more foul play going on in the game than fans realize)- "I don't know, I've never polled the guys on it. I think that there's a lot of stuff that happens in the trenches that happens. I don't know exactly how to answer that question."
(On if he got a response from the league regarding a protest of Jerome Harrison's fumble call last Sunday and if it is something he can share)- "They do answer the questions, but that stays internal. We do get answers."
(On if he can say what the league's response was)- "I'd much rather leave it internal."
(On if he feels that he needs a spark from someone on the offense)- "I feel like we've had sparks and I think turnovers pour water on it. I think that penalties pour water on it. You're moving the ball and suddenly, you're moving backwards. It's hard. Those are momentum changers in the short term where you have a good drive going and you get one of those deals and now you have got to start all over again. It changes field position. You're punting from a different spot. Instead of third and five, it's third and 20. You have got to overcome those 15 yards with the punt or they're getting the ball 15 yards closer than they should have. I don't view it as someone needs to make a play as much as I view it as us making sure that we make the plays that are there and don't set ourselves back with penalties or turnovers. A lot of different guys have touched the ball, a lot of different guys have done positive things with the ball in their hands. Now it's consistency and maintaining the drives. If the drive does get stalled, we are punting from where we should punt from as opposed to putting from backed up. A 15-yard swing in field position or a 10-yard swing in field position, it's challenging. It's going to be the difference between them being backed up or them being on the 20, 25 or 30 yard line."
(On if Tony Pashos was kept off of the field because team's don't normally rotate offensive linemen)- "Tony played a little bit this week. As we talked about it, I have confidence in Tony. If he goes in the game, I expect him to play well. I have confidence in Floyd (Womack) and John (St. Clair) as well. I think that's a positive situation. Unfortunately, it's not like a nickel defense or something where you've got a guy that plays that spot and you can just roll him in. We'll do some of it, it's not something that's built in every other drive or things like that. I'm not opposed to Tony getting more reps or anything like that. I think when he goes in, he'll do well."
(On Pashos being at tackle and St. Clair being at guard a little bit last week)- "At that point, I wanted to give Floyd a blow and that's why we worked it in. I don't think we will go into each game saying, 'Okay, the first three series will be this guy. The next three series will be that guy.' I don't expect that to be the approach."
(Subscriber) Scouting UNC: Q&A with coach Butch Davis: Rutgers hosts North Carolina in its biggest test of the you… http://bit.ly/asoVAS
Wallace Free to Roam: Seneca Wallace may get the nod for the second consecutive week Sunday at Baltimore. On Wedne… http://bit.ly/byUU1g
That price couldn't have been set while sober -> @MarcSessler Braylon charges fans $55 for a "The Beard" T-shirt on his Web site.
@NFLSoupKeet I don't see the Eagles dealing Kolb during the season. You have to have a strong backup QB in the NFL.
@Ericflong We post the press conference transcripts in the OBR Daily Blog. The URL changes every day, but I may have a way to fix that.
Baltimore Can Be Defeated
Don Delco on September 22nd, 2010 AT 11:20 AM
After two losses to start the season, once again, the sky is falling in Brownstown. This coach is an idiot. That player stinks. Those responses are nothing new.
To make matters worse, the Browns travel to Baltimore on Sunday where since 1999, the Ravens are 101-77 with a Super Bowl win. It is not a good time for the Ravens to be the Browns opponent. Cleveland's fan base is angered and the sight of Baltimore brings up bad memories.
But the Browns can win on Sunday. It may seem silly to read such things considering the Browns haven't beaten the Ravens since 2007. Hang on.
In two games, the Ravens offense has struggled. Sure, the Jets defense is good, but last week in a 15-10 loss to Cincinnati, quarterback Joe Flacco was 17-for-39 passing for 154 with one touchdown and four interceptions and the running game had only 109 yards on 23 carries.
Meanwhile, the Browns defense has played well. They have not allowed a player to reach the 100-yard rushing plateau in four consecutive games and the Browns are one of eight teams in the NFL not to allow a rushing touchdown this season. Opponents are averaging 3.7 yards per carry and 170.5 yards passing per game. Safety T.J. Ward has a team-high 19 tackles and highlights an emerging secondary. Also, pressure is being applied to the quarterback as evident by linebacker Marcus Benard's team-high 2.5 sacks.
Sure the Browns scored three points in two meetings against Baltimore last season and they have yet to put points on the board in the second half this season. Defense can win games. If the Browns defense comes to play against a questionable Ravens offense on Sunday … the Browns can win this game.
Moore will miss practice. Mangini confirmed he had a concussion.
Jake rogers lauvao smith will not practice wed.
Latest Links from the OBR Newswire
OBR Newswire on September 22nd, 2010 AT 9:00 AM
These are links from the OBR Newswire for September 22nd from 08:12 to 08:16:
- Akron Beacon Journal – Browns' Maiava out for season – The Browns placed linebacker Kaluka Maiava on injured reserve and re-signed linebacker Titus Brown off the Denver Broncos' practice squad, the team announced Tuesday.
- Plain Dealer – Can Joe Flacco reward Baltimore Ravens' confidence? – The Baltimore Ravens made a major decision this year in putting their Super Bowl hopes in the hands of their quarterback. The shift in their philosophy occurred in February when owner Steve Bisciotti publicly challenged Joe Flacco to step up his game in Year 3.
- Canton Repository – D'Qwell Jackson hopes it's not too late to save season – This little town has two "DQs," one specializing in frozen treats, one whose business is stopping men cold.
- News-Herald – Test toughens for run game – Nothing is wrong with the Browns' sluggish running attack more practice won't cure, according to center Alex Mack.
- News Herald – Thomas doesn't dwell on losses (with two videos) – Do you think you felt bad after the Browns' loss on Sunday? It's safe to say Browns left tackle Joe Thomas felt worse.
- NFL FanHouse – Browns Seek 60-Minute Solution – For two consecutive weeks, the Cleveland Browns (0-2) were on top of their game in the first half offensively. But in the second half, the execution that was there in the first 30 minutes of the contest simply disappeared. Maybe it's the halftime Gatorade and if that's the issue, give them some water.
- Dayton Daily News – Any wins on the horizon? – As I watched the Browns lose Sunday in a Mexican restaurant eating a chimichanga served to me by a gal in a Bengals jersey (it's supposed to be largely a Browns bar!!!!), I was struck by the fact that this team isn't very good.
- CBSSports.com – Running game no longer essential in recipe for success – People keep telling me that football teams must run to be successful, and I keep asking them how come the 2009 Indianapolis Colts didn't get the message. I mean, when you rank last in rushing you shouldn't be able to go anywhere in January but the next tee, right? Yet the Colts did. They went to the Super Bowl.
Zeppe's Pizzeria OBR Radio: 9/21 Podcast: Fred, Barry, Stef, and Lane contemplate how to climb out of a deep, dark… http://bit.ly/9heehf
Zeppe's Pizzeria OBR Radio: 9/21 Podcast: Fred, Barry, Stef, and Lane contemplate how to climb out of a deep, dark… http://bit.ly/9heehf
@3_Dots I think Bababooey is referring to Braylon's DWI arrest last night. He blew a .16… impressive!
Titus Brown Swiped Back from Broncos: Hot News for LB Titus Brown http://bit.ly/9JMKer
(Subscriber) Adkins: Tough Questions Pt. 2: Lane Adkins addresses even more questions in today's second installmen… http://bit.ly/b4TVQk


text:
Ultimate - Touch Me Baby 12" extented MP3
From the album The Casablanca Records Story. (NO INFRINGEMENT OF COPYRIGHT IS INTENDED)
คือ นั่งทำไปฟินไปอะเทอ-..- 555555555 ดูแล้วไลค์ด้วยน๊าาาา ♥ จุ้บ.
Brokenbeatz - Touch Me Baby (Mr Bronkz Remix) MP3
Dla Kochanego Koteczka ..:**
Brokenbeatz - Touch Me Baby (Mr Bronkz Remix) MP3
Music House.
Bloodhound Gang - The Bad Touch MP3
Music video by Bloodhound Gang performing The Bad Touch. (C) 1999 Interscope Records.
The Bad Touch
Bloodhound GangHa-ha! Well now, we call this the act of mating But, there are several other very important differences between human beings and animals that you should know about I'd appreciate your input Sweat, baby, sweat, baby, sex is a Texas drought Me and you do the kind of stuff that only Prince would sing about So p[...]
Formato:Vinilo, 12 " País : Suiza Fecha de lanzamiento : 1989 Género : Electrónico Estilo : Italo-Disco.
Static 3 - Touch Me Baby (Dj's Dub) MP3
Xtreme - Touch Me Baby featuring Tot-Lina MP3
Xtreme - Touch Me Baby featuring Tot-Lina เพลงลาว ເພງລາວ.
The Doors - Touch me baby MP3
The Doors. After each door is a room to another door and to another... waiting to be explored. The only thing is if you really, really want to look for all those keys ...
Sharon - Touch Me Baby (Italo Energy) MP3
High Energy Italo.
1986 The Temptations / Do You Really Love Your Baby - Touch Me (Live ) on Black & Gold Award MP3
Freddie Hubbard - Touch Me Baby (1976) MP3
Backing Vocals -- Frank Floyd, Gwen Guthrie, Patti Austin, Vivian Cherry, Zach Sanders Bass -- Gary King Cello -- Charles McCracken, Jesse Levy Drums ...
The Doors - Touch Me ( lyrics ) MP3
Yeah! Come on, come on, come on, come on Now touch me, baby Can't you see that I am not afraid? What was that promise that you made? Why won't you tell ...
touch me baby in the best way MP3
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Ultimate - Touch Me Baby MP3
Ultimate - Touch Me Baby.
Ultimate - Love Is The Ultimate/Touch Me Baby/Dancing In The Night MP3
Discos CASABLANCA u.s.a. 1979.
Myrna Hague - Touch Me Baby MP3
Studio One Lovers 2005 Visita: https://www.facebook.com/PADRINO.SKA.CLUB.
Sharon - touch me baby MP3
Sharon touch me baby very nice 80's song.
Myrna Hague - "Touch Me Baby" MP3
Studio One / Late 1970s.
The Doors In Concert - Touch me baby MP3
Touch me baby - The Doors in Concert - theatre tour october 2011 - Vianen Stadshoftheater - Authentic Tribute band - original line up, original instruments and ...
Ledina Çelo - Can you touch me baby (Official Video) MP3
Producer & Rightsholder: Ledina Çelo Facebook: http://www.facebook.com/ArkivaShqip.
Touch me baby speedpaint MP3
xD oh yeah sweetie wants the D and i am so sorry that my screen recorder did not work right :( i think its because i deleted my watermark off of my desktop Song: ...
TITO SIMON - TOUCH ME BABY - Reggae MP3
Tito Simon - Touich Me Baby When The Heat Is On / Pearl Records I do not own any rights to this song for entertainment purpose`s only No copyright ...
U-Kiss - Baby, touch me budokan ELVIN Sub Español + romanization MP3
baby touch me en el concierto de budokan.
Ultimate - "Touch Me Baby" (1978) MP3
Featung The Solid Gold Dancers: Darcel Wynne, Deborah Jenssen, Helene Phillips, Pamela Rossi, Kahea Bright, Paula Beyers, Gayle Crofoot, Alexander Cole, ...
Xtreme - Touch Me Baby (Official Lyric Video) MP3
The 4th single release of KPY's successful boy band, Xtreme! "Touch Me Baby". © KPY Entertainent 2012.
Ultimate - Love Is The Ultimate, Dancin In The Night,Touch Me Baby (1978) MP3
Dj Cole's Disco Classics. Ultimate - Love Is The Ultimate, Dancin In The Night,Touch Me Baby. This Earth Shattering Monster 1978 Disco Hit Was Played To ...
Mariah Carey - Touch My Body MP3
Music video by Mariah Carey performing Touch My Body. (C) 2008 The Island Def Jam Music Group and Mariah Carey.
Touch My Body
Mariah CareyMC, in the place to be Oh, yeah, oh, yeah, oh, yeah, oh, yeah, oh, yeah, oh, yeah, oh, yeah I know that you been waitin' for me, and I'm waitin', too In my imagination, I be all up on you I know you got that fever for me, hundred and two And, boy, I know I feel the same, my temperature's through the roof If there's a camera up in here then it's gonna leave[...]


text:
Actor Aamir Khan wore a bowler hat in his film 'Dhoom 3'. Immediately, it became a style statement. A lot of stars like Salman Khan, Kareena Kapoor and others started wearing a hat.
The young brigade seems to be one step ahead, when it comes to supporting their colleagues.
Sushant Singh Rajput, who will be playing the role of Detective Byomkesh Bakshy in his upcoming film, has been frequently seen these days, wearing his film attire in a fushion style.
Also Read: Catch Movies 1st Day, 1st Show, absolutely FREE!! Click here to know more.
Sushant, who wore a dhoti for his entire shoot, finds it very cool. In fact, he even insisted his stylist to come up with innovative ideas for dhoti, which he has been donning for all the promotional and big events. Everyone at Yash Raj Films have been discussing as to, how one should wear the dhoti in the most stylist manner.Whoever has seen the rushes of the film, have been appreciating Sushant. Recently, Arjun Kapoor has come out in support of Sushant Singh Rajput. He shares a great bond with Sushant. When he saw a glimpse of the film, he instantly liked it. The two even spoke about the desi touch of dhoti.
Arjun even told Sushant that he would also don a dhoti, the next time he goes to an event. Staying true to his words, Arjun recently wore a dhoti for an event.
Looks like this fashion season, the dhoti is all set to become the next cool!
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