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)

APOE4 homozygosity has been associated with an increased risk of sporadic Alzheimer's disease through a mechanism, which has yet to be defined. Recent evidence has suggested that microvascular basement membrane injury may be a critical factor in the pathogenesis of AD-related dementia. In previous studies, we have shown that the synaptic organizing protein agrin can be found in neurons, and is a major component of the brain microvascular basement membrane. Here, we compare the basement membrane surface area of cortical microvasculature in AD brains by staining with an anti-agrin antibody. Quantitative morphometric analysis was used to determine the mean basement area (micro(2)) of prefrontal cortical microvessels. An average of 10 capillaries was measured in each of 35 cases of AD genotyped for APOE status. APOE4,4 homozygotes had smaller capillary basement membrane areas (17.4 micro(2))+/-6.2) than APOE3,3 homozygotes (26.9 micro(2)+/-6.5), p<0.001. The capillary basement membrane areas (CBMA) of heterozygotes APOE3,4 did not differ significantly from APOE3,3 or APOE4,4. Braak stage did not contribute significantly to CBMA. However, a preliminary analysis suggests an interaction between APOE4,4 and Braak V-VI producing smaller CBMA, a finding which needs to be confirmed with a larger sample. These data support the hypothesis that APOE4,4 is associated with thinning of the microvascular basement membrane in Alzheimer's disease.
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PMID:Effect of APOE genotype on microvascular basement membrane in Alzheimer's disease. 1241 81

The MARK protein kinases were originally identified by their ability to phosphorylate a serine motif in the microtubule-binding domain of tau that is critical for microtubule binding. Here, we report the cloning and expression of a novel human paralog, MARK4, which shares 75% overall homology with MARK1-3 and is predominantly expressed in brain. Homology is most pronounced in the catalytic domain (90%), and MARK4 readily phosphorylates tau and the related microtubule-associated protein 2 (MAP2) and MAP4. In contrast to the three paralogs that all exhibit uniform cytoplasmic localization, MARK4 colocalizes with the centrosome and with microtubules in cultured cells. Overexpression of MARK4 causes thinning out of the microtubule network, concomitant with a reorganization of microtubules into bundles. In line with these findings, we show that a tandem affinity-purified MARK4 protein complex contains alpha-, beta-, and gamma-tubulin. In differentiated neuroblastoma cells, MARK4 is localized prominently at the tips of neurite-like processes. We suggest that although the four MARK/PAR-1 kinases might play multiple cellular roles in concert with different targets, MARK4 is likely to be directly involved in microtubule organization in neuronal cells and may contribute to the pathological phosphorylation of tau in Alzheimer's disease.
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PMID:MARK4 is a novel microtubule-associated proteins/microtubule affinity-regulating kinase that binds to the cellular microtubule network and to centrosomes. 1459 45

An insertion test (Shift vs. non-Shift) was performed by eight subjects (mean age 69 years, mean schooling 5.87 years) with clinical diagnosis of suspected Alzheimer disease (AD) in order to reveal right hemisphere cerebral distress in concomitance with damage of the left hemisphere which controls language in AD. Their Shift and non-Shift test scores were significantly lower than those of 28 controls, even if they achieved normal or slightly modified classical language test scores. Shift involves insertion of a syntagma or word in a stimulus-sentence that changes the syntactical relationship of some components of the newly formed sentence, whereas in non-Shift the insertion determines only a change in meaning. Statistical analysis revealed that the difference was not caused by age and schooling. Furthermore, the AD patients achieved significantly lower scores in Shift compared with non-Shift. This indicates greater right hemisphere damage in these patients and confirms its physiological decline in the elderly. The results revealed that the insertion test is more sensitive than classical neurolinguistic tests. They also showed that both superficial (non-Shift) and deep (Shift) types of syntaxes are already compromised in early stages of AD and that they mirror the bilateral thinning which is more pronounced in the right hemisphere.
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PMID:Study of the language functions controlled by the right hemisphere in patients affected by dementia. 1537 27

The cerebral cortex undergoes changes during normal ageing with increasing effect on cognition. Disruption of minicolumnar organization of neurons is found with increased cognitive impairment in primates. We measured the minicolumn spacing and organization of cells in Heschl's gyrus (primary auditory cortex, A1), the Planum Temporale (Tpt, BA22), and middle temporal gyrus (MTG, BA21) of 17 normally aged human adults. Age-associated minicolumn thinning was found in temporal lobe association cortex (Tpt and MTG) but not primary auditory cortex (HG). Minicolumn thinning was also associated with greater plaque load, although this effect was present in all areas. The regional variability of age-associated minicolumn thinning reflects the regionally selective progression of tangle pathology in Alzheimer's Disease (AD). The generalized effect of plaque load persists when controlling for age. Therefore plaque load combines with age to increase minicolumn thinning, which may reflect increasing risk of AD. Since old age is the greatest risk factor for dementia, the transition to dementia may involve an extension of normal ageing processes.
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PMID:Minicolumn thinning in temporal lobe association cortex but not primary auditory cortex in normal human ageing. 1649 64

Thinning and discontinuities within the vascular basement membrane (VBM) are associated with leakage of the plasma protein prothrombin across the blood-brain barrier (BBB) in Alzheimer's disease (AD). Prothrombin immunohistochemistry and ELISA assays were performed on prefrontal cortex. In severe AD, prothrombin was localized within the wall and neuropil surrounding microvessels. Factor VIII staining in severe AD patients indicated that prothrombin leakage was associated with shrinkage of endothelial cells. ELISA revealed elevated prothrombin levels in prefrontal cortex AD cases that increased with the Braak stage (Control=1.39, I-II=1.76, III-IV=2.28, and V-VI=3.11 ng prothrombin/mg total protein). Comparing these four groups, there was a significant difference between control and Braak V-VI (p=0.0095) and also between Braak stages I-II and V-VI (p=0.0048). There was no significant difference in mean prothrombin levels when cases with versus without cerebral amyloid angiopathy (CAA) were compared (p-value=0.3627). When comparing AD patients by APOE genotype (ApoE3,3=2.00, ApoE3,4=2.49, and ApoE4,4=2.96 ng prothrombin/mg total protein) an analysis of variance indicated a difference between genotypes at the 10% significance level (p=0.0705). Tukey's test indicated a difference between the 3,3 and 4,4 groups (p=0.0607). These studies provide evidence that in advanced AD (Braak stage V-VI), plasma proteins like prothrombin can be found within the microvessel wall and surrounding neuropil, and that leakage of the blood-brain barrier may be more common in patients with at least one APOE4 allele.
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PMID:Microvascular injury and blood-brain barrier leakage in Alzheimer's disease. 1678 34

Cortical thickness is a more reliable measure of atrophy than volume due to the low variability in the cytoarchitectural structure of the grey matter. However, this more desirable measure of disease-related alterations is not fully evaluated in early dementia. The study presented here is the first to report the spatial patterns of cortical thickness in the pre-clinical stages of Alzheimer's disease, namely mild cognitive impairment (MCI). Cortical thickness measurements for 34 healthy elderly, 62 MCI and 42 Alzheimer's disease subjects were made using fully automated magnetic resonance imaging-based analysis techniques in order to determine the pattern of cortical thinning as a function of disease progression. The thickness of the cortex decreased significantly when the healthy elderly brains were compared to those with MCI, mainly in the medial temporal lobe region and in some regions of the frontal and the parietal cortices. With the progression of disease from MCI to Alzheimer's disease, a general thinning of the entire cortex with significant extension into the lateral temporal lobe was found. In all cases, the results were more pronounced in the left hemisphere. In conclusion, we have shown that there is a specific pattern in the thinning of the cortical ribbon which is in agreement with the previous histological reports. These novel findings support the notion of increased isocortical involvement with the progression of disease.
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PMID:Spatial patterns of cortical thinning in mild cognitive impairment and Alzheimer's disease. 1700 32

The amyloid hypothesis of Alzheimer's toxicity has undergone a resurgence with increasing evidence that it is not amyloid fibrils but a smaller oligomeric species that produces the deleterious results. In this paper we address the mechanism of this toxicity. Only oligomers increase the conductance of lipid bilayers and patch-clamped mammalian cells, producing almost identical current-voltage curves in both preparations. Oligomers increase the conductance of the bare bilayer, the cation conductance induced by nonactin, and the anion conductance induced by tetraphenyl borate. Negative charge reduces the sensitivity of the membrane to amyloid, but cholesterol has little effect. In contrast, the area compressibility of the lipid has a very large effect. Membranes with a large area compressibility modulus are almost insensitive to amyloid oligomers, but membranes formed from soft, highly compressible lipids are highly susceptible to amyloid oligomer-induced conductance changes. Furthermore, membranes formed using the solvent decane (instead of squalane) are completely insensitive to the presence of oligomers. One simple explanation for these effects on bilayer conductance is that amyloid oligomers increase the area per molecule of the membrane-forming lipids, thus thinning the membrane, lowering the dielectric barrier, and increasing the conductance of any mechanism sensitive to the dielectric barrier.
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PMID:Soluble amyloid oligomers increase bilayer conductance by altering dielectric structure. 1713 May 16

Effects of APOE genotype on age-related slopes of cortical thinning was estimated by measuring the thickness of the cerebral cortex on a point-by-point basis across the cortical mantle in 96 healthy non-demented volunteers aged 48-75 years. Fifty nine were APOE epsilon 4- (no epsilon 4 allele) and 37 were epsilon 4+ (1 or 2 epsilon 4 alleles). The genotype groups had similar age, sex and IQ. Two T(1)-weighted MP-RAGE sequences were averaged for each participant to yield images with high signal-to-noise ratio, and quantified using semi-automated analysis tools. epsilon 4 carriers had thicker cortex than non-carriers in several frontal and temporal areas in both hemispheres, but showed a steeper age-related decline in adjacent areas. Upon comparison of the epsilon 4-specific age-related thinning with previously published patterns of thinning in normal aging and Alzheimer's disease (AD), we conclude that APOE epsilon 4 may function to accelerate thinning in areas found to decline in aging (medial prefrontal and pericentral cortex), but also to initiate thinning in areas associated with AD and amyloid-beta aggregation (occipitotemporal and basal temporal cortex).
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PMID:Accelerated age-related cortical thinning in healthy carriers of apolipoprotein E epsilon 4. 1716 8

Subtle changes in the human brain constitute a third element in addition to plaques and tangles as markers of vulnerability to Alzheimer's disease (AD). Neurofibrillary tangle (NFT) distribution shows the closest relationship to the severity of dementia. Two features of the distribution (regional selectivity and columnar clustering) provide clues about the structural changes due to normal ageing that may precede tangle formation. It is hypothesized that the columnar organization of the cortex, determines the pattern of pathological spread in AD and, consequently, the pattern of function loss. Minicolum thinning occurs in normal ageing and echoes the selective regional distribution of NFT formation in AD. NFT vulnerability appears to emerge from hierarchical variation in neural plasticity associated with the hierarchical variation in size and spacing of mini and macro-columns in the cortex. Regional differences may involve regional variation in gene expression. Dietary Omega 3 fatty acid intake has been shown to have neuroprotective effects on the cytoarchitectural features that contribute to this cortical hierarchy.
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PMID:Subtle changes in the ageing human brain. 1718 Aug 66

Alzheimer's disease and frontotemporal dementia (FTD) can be difficult to differentiate clinically because of overlapping symptoms. Distinguishing the two dementias based on volumetric measurements of brain atrophy with MRI has been only partially successful. Whether MRI measurements of cortical thinning improve the differentiation between Alzheimer's disease and FTD is unclear. In this study, we measured cortical thickness using a set of automated tools (Freesurfer) to reconstruct the brain's cortical surface from T1-weighted structural MRI data in 22 patients with Alzheimer's disease, 19 patients with FTD and 23 cognitively normal subjects. The goals were to detect the characteristic patterns of cortical thinning in these two types of dementia, to test the relationship between cortical thickness and cognitive impairment, to determine if measurement of cortical thickness is better than that of cortical volume for differentiating between these dementias and normal ageing and improving the classification of Alzheimer's disease and FTD based on neuropsychological scores alone. Compared to cognitively normal subjects, Alzheimer's disease patients had a thinner cortex primarily in bilateral, frontal, parietal, temporal and occipital lobes (P < 0.001), while FTD patients had a thinner cortex in bilateral, frontal and temporal regions and some thinning in inferior parietal regions and the posterior cingulate (P < 0.001). Compared to FTD patients, Alzheimer's disease patients had a thinner cortex (P < 0.001) in parts of bilateral parietal and precuneus regions. Cognitive impairment was negatively correlated with cortical thickness of frontal, parietal and temporal lobes in Alzheimer's disease, while similar correlations were not significant in FTD. Measurement of cortical thickness was similar to that of cortical volume in differentiating between normal ageing, Alzheimer's disease and FTD. Furthermore, cortical thickness measurements significantly improved the classification between Alzheimer's disease and FTD based on neuropsychological scores alone, including the Mini-Mental State Examination and a modified version of the Trail-Making Test. In conclusion, the characteristic patterns of cortical thinning in Alzheimer's disease and FTD suggest that cortical thickness may be a useful surrogate marker for these types of dementia.
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PMID:Different regional patterns of cortical thinning in Alzheimer's disease and frontotemporal dementia. 1735 26


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