Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0851184 (thinning)
 11,252 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Understanding the pathogenicity of amyloid-beta (Abeta) peptides constitutes a major goal in research on Alzheimer's disease (AD). One hypothesis entails that Abeta peptides induce uncontrolled, neurotoxic ion flux through cellular membranes. The exact biophysical mechanism of this ion flux is, however, a subject of an ongoing controversy which has attenuated progress toward understanding the importance of Abeta-induced ion flux in AD. The work presented here addresses two prevalent controversies regarding the nature of transmembrane ion flux induced by Alphabeta peptides. First, the results clarify that Alphabeta can induce stepwise ion flux across planar lipid bilayers as opposed to a gradual increase in transmembrane current; they show that the previously reported gradual thinning of membranes with concomitant increase in transmembrane current arises from residues of the solvent hexafluoroisopropanol, which is commonly used for the preparation of amyloid samples. Second, the results provide additional evidence suggesting that Abeta peptides can induce ion channel-like ion flux in cellular membranes that is independent from the postulated ability of Alphabeta to modulate intrinsic cellular ion channels or transporter proteins.
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PMID:Amyloid-beta-induced ion flux in artificial lipid bilayers and neuronal cells: resolving a controversy. 1952 94

Disruption of the postsynaptic density (PSD), a network of scaffold proteins located in dendritic spines, is thought to be responsible for synaptic dysfunction and loss in early-stage Alzheimer's disease (AD). Extending our previous demonstration that derangement of the PSD by soluble amyloid-beta (Abeta) involves proteasomal degradation of PSD-95, a protein important for ionotropic glutamate receptor trafficking, we now show that Abeta also disrupts two other scaffold proteins, Homer1b and Shank1, that couple PSD-95 with ionotropic and metabotropic glutamate receptors. Treatment of fronto-cortical neurons with soluble Abeta results in rapid (within 1 h) and significant thinning of the PSD, decreased synaptic levels of Homer1b and Shank1, and reduced synaptic mGluR1 levels. We show that de novo protein synthesis is required for the declustering effects of Abeta on Homer1b (but not Shank1) and that, in contrast to PSD-95, Abeta-induced Homer1b and Shank1 cluster disassembly does not depend on proteasome activity. The regulation of Homer1b and Shank1 by Abeta diverges in two other respects: i) whereas the activity of both NMDAR and VDCC is required for Abeta-induced declustering of Homer1b, Abeta-induced declustering of Shank1 only requires NMDAR activity; and ii) whereas the effects of Abeta on Homer1b involve engagement of the PI-3K pathway and calcineurin phosphatase (PP2B) activity, those on Shank1 involve activation of the ERK pathway. In summary, soluble Abeta recruits discrete signalling pathways to rapidly reduce the synaptic localization of major components of the PSD and to regulate the availability of mGluR1 in the synapse.
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PMID:Disassembly of shank and homer synaptic clusters is driven by soluble beta-amyloid(1-40) through divergent NMDAR-dependent signalling pathways. 1954 99

A significant minority of Alzheimer's disease patients present with posterior cortical atrophy (PCA). PCA is characterized by visuospatial and visuoperceptual deficits, and relatively preserved memory, whereas patients with typical Alzheimer's disease (tAD) mostly present with early episodic memory deficits. We used two unbiased image analysis techniques to assess atrophy patterns in 48 PCA, 30 tAD, and 50 healthy controls. FreeSurfer was used to measure cortical thickness, and volumetric grey matter differences were assessed using voxel-based morphometry (VBM). Both PCA and tAD showed widespread reductions compared with controls using both techniques. Direct comparison of PCA and tAD revealed thinner cortex predominantly in the right superior parietal lobe in the PCA group compared with tAD, whereas the tAD group showed thinning in the left entorhinal cortex compared with PCA. Similar results were obtained in the VBM analysis. These distinct patterns of atrophy may have diagnostic utility. In a clinical context, a relatively spared medial temporal lobe in the presence of posterior parietal atrophy may imply PCA, and should not discount AD.
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PMID:Cortical thickness and voxel-based morphometry in posterior cortical atrophy and typical Alzheimer's disease. 1978 14

An accurate description of changes in the brain in healthy aging is needed to understand the basis of age-related changes in cognitive function. Cross-sectional magnetic resonance imaging (MRI) studies suggest thinning of the cerebral cortex, volumetric reductions of most subcortical structures, and ventricular expansion. However, there is a paucity of detailed longitudinal studies to support the cross-sectional findings. In the present study, 142 healthy elderly participants (60-91 years of age) were followed with repeated MRI, and were compared with 122 patients with mild to moderate Alzheimer's disease (AD). Volume changes were measured across the entire cortex and in 48 regions of interest. Cortical reductions in the healthy elderly were extensive after only 1 year, especially evident in temporal and prefrontal cortices, where annual decline was approximately 0.5%. All subcortical and ventricular regions except caudate nucleus and the fourth ventricle changed significantly over 1 year. Some of the atrophy occurred in areas vulnerable to AD, while other changes were observed in areas less characteristic of the disease in early stages. This suggests that the changes are not primarily driven by degenerative processes associated with AD, although it is likely that preclinical changes associated with AD are superposed on changes due to normal aging in some subjects, especially in the temporal lobes. Finally, atrophy was found to accelerate with increasing age, and this was especially prominent in areas vulnerable to AD. Thus, it is possible that the accelerating atrophy with increasing age is due to preclinical AD.
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PMID:One-year brain atrophy evident in healthy aging. 1995 75

Here, we examine morphological changes in cortical thickness of patients with Alzheimer's disease (AD) using image analysis algorithms for brain structure segmentation and study automatic classification of AD patients using cortical and volumetric data. Cortical thickness of AD patients (n=14) was measured using MRI cortical surface-based analysis and compared with healthy subjects (n=20). Data was analyzed using an automated algorithm for tissue segmentation and classification. A Support Vector Machine (SVM) was applied over the volumetric measurements of subcortical and cortical structures to separate AD patients from controls. The group analysis showed cortical thickness reduction in the superior temporal lobe, parahippocampal gyrus, and enthorhinal cortex in both hemispheres. We also found cortical thinning in the isthmus of cingulate gyrus and middle temporal gyrus at the right hemisphere, as well as a reduction of the cortical mantle in areas previously shown to be associated with AD. We also confirmed that automatic classification algorithms (SVM) could be helpful to distinguish AD patients from healthy controls. Moreover, the same areas implicated in the pathogenesis of AD were the main parameters driving the classification algorithm. While the patient sample used in this study was relatively small, we expect that using a database of regional volumes derived from MRI scans of a large number of subjects will increase the SVM power of AD patient identification.
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PMID:Use of SVM methods with surface-based cortical and volumetric subcortical measurements to detect Alzheimer's disease. 2006 13

We use a new, unsupervised multivariate imaging and analysis strategy to identify related patterns of reduced white matter integrity, measured with the fractional anisotropy (FA) derived from diffusion tensor imaging (DTI), and decreases in cortical thickness, measured by high resolution T1-weighted imaging, in Alzheimer's disease (AD) and frontotemporal dementia (FTD). This process is based on a novel computational model derived from sparse canonical correlation analysis (SCCA) that allows us to automatically identify mutually predictive, distributed neuroanatomical regions from different imaging modalities. We apply the SCCA model to a dataset that includes 23 control subjects that are demographically matched to 49 subjects with autopsy or CSF-biomarker-diagnosed AD (n=24) and FTD (n=25) with both DTI and T1-weighted structural imaging. SCCA shows that the FTD-related frontal and temporal degeneration pattern is correlated across modalities with permutation corrected p<0.0005. In AD, we find significant association between cortical thinning and reduction in white matter integrity within a distributed parietal and temporal network (p<0.0005). Furthermore, we show that-within SCCA identified regions-significant differences exist between FTD and AD cortical-connective degeneration patterns. We validate these distinct, multimodal imaging patterns by showing unique relationships with cognitive measures in AD and FTD. We conclude that SCCA is a potentially valuable approach in image analysis that can be applied productively to distinguishing between neurodegenerative conditions.
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PMID:Dementia induces correlated reductions in white matter integrity and cortical thickness: a multivariate neuroimaging study with sparse canonical correlation analysis. 2008 7

Alzheimer's disease (AD) is the major cause of dementia in the world. Although the entorhinal cortex and hippocampal complex are best known as the sites of early pathology in AD, increasing evidence shows that the eye, particularly the retina, is also affected. The AD-related changes in the retina are associated with degeneration and loss of neurons, reduction of the retinal nerve fibres, increase in optic disc cupping, retinal vascular tortusity and thinning, and visual functional impairment. Given the fact that evaluating pathologic changes in the brain during life has always been an indirect process, largely shielded from view by the barrier of the skull, the eye can be used as a window into diseases of the brain. Using modern techniques, the changes in the retina can be visualized in real-time. In addition to the changes in the eyes of AD patients, similar mechanisms of neurodegeneration in the brain have also been demonstrated in the eye. Targeting AD-liked changes in the retina has been recently shown to be effective in the reduction of retinal neuronal degeneration and loss in eye diseases. This review will cover recent findings on retinal degeneration in AD, pathological similarities between AD and eye diseases, and highlight the potential of modern technologies for the detection of prospective biomarkers in the eye in early AD.
Curr Alzheimer Res 2010 Feb
PMID:Alzheimer's disease and retinal neurodegeneration. 2020 67

The extent of smoothing applied to cortical thickness maps critically influences sensitivity, anatomical precision and resolution of statistical change detection. Theoretically, it could be optimized by increasing the trade-off between vertex-wise sensitivity and specificity across several levels of smoothing. But to date neither parametric nor nonparametric methods are able to control the error at the vertex level if the null hypothesis is rejected after smoothing of cortical thickness maps. To overcome these drawbacks, we applied sequential statistical thresholding based on a simple hierarchical model. This methodology aims at controlling erroneous detections; firstly at the level of clusters, over smoothed statistical maps; and secondly at the vertex level, over unsmoothed statistical maps, by applying an adaptive false discovery rate (FDR) procedure to clusters previously detected. The superior performance of the proposed methodology over other conventional procedures was demonstrated in simulation studies. As expected, only the hierarchical method yielded a predictable false discovery proportion near the predefined FDR q-value for any smoothing level at the same time as being as sensitive as the others at the optimal setting. It was therefore the only method able to approximate the optimal size of spatial smoothing when the true change was assumed unknown. The hierarchical method was further validated in a cross-sectional study comparing moderate Alzheimer's disease (AD) patients with healthy elderly subjects. Results suggest that the extent of cortical thinning reported in previous AD studies might be artificially inflated by the choice of inadequate smoothing. In these cases, interpretation should be based on the location of local maxima of suprathreshold regions rather than on the spatial extent of the detected signal in the statistical parametric map.
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PMID:Determining the optimal level of smoothing in cortical thickness analysis: a hierarchical approach based on sequential statistical thresholding. 2036 77

Structural magnetic resonance imaging (MRI) of brain tissue loss and physiological imaging of regional cerebral blood flow (rCBF) can provide complimentary information for the characterization of brain disorders, such as Alzheimer's disease (AD) but studies into gains in classification power for AD using these image modalities jointly have been limited. Our aim in this study was to determine the joint contribution of structural and perfusion-weighted imaging for the classification of AD in a cross-sectional study using an integrated multimodality MRI processing framework and a cortical surface-based analysis approach. We used logistic regression analysis to determine sequentially the value of cortical thickness, rCBF, and cortical thickness and rCBF jointly for classification for diagnosis of AD compared to controls. We further tested the extent to which cortical thinning and reduced rCBF explain individually or together variability in dementia severity. Separate analysis of structural MRI and perfusion-weighted MRI data yielded the well-established pattern of cortical thinning and rCBF reduction in AD, affecting predominantly temporo-parietal brain regions. Using structural MRI and perfusion-weighted MRI jointly indicated that cortical thinning dominated the classification of AD and controls without significant contributions from rCBF. However there was also a positive interaction between reduced rCBF and cortical thinning in the right superior temporal sulcus, implying that structural and physiological brain alterations in AD can be complementary. Compared to reduced rCBF, regional cortical thinning better explained the variability in dementia severity. In conclusion, structural brain alterations compared to physiological variations are the dominant features of MRI in AD.
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PMID:Joint analysis of structural and perfusion MRI for cognitive assessment and classification of Alzheimer's disease and normal aging. 2040 91

People with the apolipoprotein-Eepsilon4 (APOE-4) genetic risk for Alzheimer's disease show morphologic differences in medial temporal lobe regions when compared to non-carriers of the allele. Using a high-resolution MRI and cortical unfolding approach, our aim was to determine the rate of cortical thinning among medial temporal lobe subregions over the course of 2 years. We hypothesized that APOE-4 genetic risk would contribute to longitudinal cortical thickness change in the subiculum and entorhinal cortex, regions preferentially susceptible to Alzheimer's disease related pathology. Thirty-two cognitively intact subjects, mean age 61 years, 16 APOE-4 carriers, 16 non-carriers, underwent baseline and follow-up MRI scans. Over this relatively brief interval, we found significantly greater cortical thinning in the subiculum and entorhinal cortex of APOE-4 carriers when compared to non-carriers of the allele. Average cortical thinning across all medial temporal lobe subregions combined was also significantly greater for APOE-4 carriers. This finding is consistent with the hypothesis that carrying the APOE-4 allele renders subjects at a higher risk for developing Alzheimer's disease.
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PMID:Longitudinal changes in medial temporal cortical thickness in normal subjects with the APOE-4 polymorphism. 2054 11


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