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PubMed1994

Beta A4-amyloid protein precursor mRNA isoforms without exon 15 are ubiquitously expressed in rat tissues including brain, but not in neurons.

The beta A4-amyloid protein precursor (APP), the source of the beta A4-amyloid deposits found in Alzheimer brains, constitutes a family of transmembrane glycoproteins generated by alternative splicing. While exon 7 and exon 8 are well known to be alternatively spliced, APP mRNA isoforms without exon 15 were only recently identified in leukocytes and rat brain microglial cells and therefore denoted as L-APP mRNAs. In order to perform a detailed analysis of individual L-APP mRNA isoforms in perfused rat tissues, we developed a quantitative polymerase chain reaction assay from reverse transcribed RNA allowing us to analyze the alternatively spliced region in between exon 6 and 16. In all peripheral tissues examined, L-APP mRNA isoforms were detected comprising between 25% (skeletal muscle) and about 70% (aorta, pancreas) of total APP transcripts. All four possible APP mRNA isoforms without exon 15 were shown to exist, i.e. L-APP752, L-APP733, L-APP696, and L-APP677. L-APP expression in the central nervous system (approximately 4% of total APP mRNA) was then studied in more detail by analyzing different brain regions and tissues and primary cultured brain cells. The only cell type which was shown not to express L-APP mRNA to a detectable level is the neuronal cell. Ubiquitous expression of APP mRNAs lacking exon 15 except for neurons indicates an important function in non-neuronal cells and is especially remarkable since neurons are the primarily affected cells in Alzheimer's disease.

Alternative Splicing↗
PubMed1998

Differential level of platelet amyloid beta precursor protein isoforms: an early marker for Alzheimer disease.

OBJECTIVE: To determine whether a differential level of platelet amyloid beta precursor protein (APP) isoforms is specifically related to Alzheimer disease (AD) and whether it shows a correlation with the progression of clinical symptoms. DESIGN: After subjects were grouped according to diagnosis and severity of dementia, APP isoform levels in platelets were compared. SETTING: University medical centers. PATIENTS: Thirty-two patients who fulfilled diagnostic criteria for probable AD, 25 age-matched control subjects, and 16 patients with non-AD dementia. MAIN OUTCOME MEASURE: The levels of APP isoforms were evaluated by means of Western blot analysis and immunostaining of whole platelets. Messenger RNAs for APP transcripts were also evaluated by means of reverse transcriptase polymerase chain reaction. RESULTS: The ratio between the intensity of the 130-kd and 106- to 110-kd APP isoforms was significantly lower in the AD group (0.31 +/- 0.15, mean +/- SD) compared with both controls (0.84 +/- 0.2) and non-AD subjects (0.97 +/- 0.4). The ratio of platelet APP isoforms in patients with AD grouped by Clinical Diagnostic Rating score significantly correlated with the severity of the disease (Pearson correlation coefficient, followed by Bonferroni correction, P = .01). Reverse transcriptase polymerase chain reaction experiments showed that APP transcripts in all experimental groups were equally expressed. CONCLUSIONS: The pattern of platelet APP isoforms is specifically altered in patients with AD. In addition, the alteration of platelet APP isoforms shows a positive correlation with the progression of clinical symptoms, supporting the possibility to consider this peripheral parameter as a marker of progression of the disease. These alterations are not related to abnormalities of APP isoforms messenger RNAs in platelets.

Adult↗
PubMed1998

Twofold overexpression of human beta-amyloid precursor proteins in transgenic mice does not affect the neuromotor, cognitive, or neurodegenerative sequelae following experimental brain injury.

By using transgenic mice that overexpress human beta-amyloid precursor proteins (APPs) at levels twofold higher than endogenous APPs, following introduction of the human APP gene in a yeast artificial chromosome (YAC), we examined the effects of controlled cortical impact (CCI) brain injury on neuromotor/cognitive dysfunction and the development of Alzheimer's disease (AD)-like neuropathology. Neuropathological analyses included Nissl-staining and immunohistochemistry to detect APPs, beta-amyloid (Abeta), neurofilament proteins, and glial fibrillary acidic protein, whereas Abeta levels were measured in brain homogenates from mice subjected to CCI and control mice by using a sensitive sandwich enzyme-linked immunosorbent assay. Twenty APP-YAC transgenic mice and 17 wild type (WT) littermate controls were anesthetized and subjected to CCI (velocity, 5 m/second; deformation depth, 1 mm). Sham (anesthetized but uninjured) controls (n = 10 APP-YAC; n = 8 WT) also were studied. Motor function was evaluated by using rotarod, inclined-plane, and forelimb/hindlimb flexion tests. The Morris water maze was used to assess memory. Although CCI induced significant motor dysfunction and cognitive deficits, no differences were observed between brain-injured APP-YAC mice and WT mice at 24 hours and 1 week postinjury. By 1 week postinjury, both cortical and hippocampal CA3 neuron loss as well as extensive astrogliosis were observed in all injured animals, suggesting that overexpression of human APPs exhibited no neuroprotective effects. Although AD-like pathology (including amyloid plaques) was not observed in either sham or brain-inj ured animals, a significant decrease in brain concentrations of only Abeta terminating at amino acid 40 (Abeta x-40) was observed following brain injury in APP-YAC mice (P < 0.05 compared with sham control levels). Our data show that the APP-YAC mice do not develop AD-like neuropathology following traumatic brain injury. This may be because this injury does not induce elevated levels of the more amyloidogenic forms of human Abeta (i.e., Abeta x-42/43) in these mice.

Amyloid beta-Peptides↗
PubMed1996

Amyloid precursor protein truncated at any of the gamma-secretase sites is not cleaved to beta-amyloid.

beta A4 secretion occurs upon processing of amyloid protein precursor (APP) by beta-secretase (N-terminus of beta A4) and gamma-secretase (C-terminus). To determine the sequence of these activities and the processing intermediate of beta A4, we expressed several truncated APP molecules in human HEK-293 cells. Immunofluorescence and biotinylation studies indicated that full-length APP or APP lacking the cytosolic domain both were located intracellularly, associated with the cell surface and secreted. APPs truncated after amino acid 40, 42, or 43 of beta A4 were not inserted into cell membranes, were found intracellularly but not on the cell surface, and were efficiently secreted into the culture medium. The secretion of APP truncated at amino acid 40 of beta A4 occurred without proteolytic processing. Neither beta A4 nor P3 (the product of the alpha-secretase) was secreted from any of the APP molecules truncated at the gamma-secretase sites. In sharp contrast to this, when the C-terminal 100 amino acids of APP were expressed (APP truncated at the N-terminus of beta A4), a robust beta A4 secretion was observed. Thus, the C-terminal fragment of APP produced by beta-secretase activity is likely to be the processing intermediate of beta A4.

Amino Acid Sequence↗
PubMed1994

Age and damage induced changes in amyloid protein precursor immunohistochemistry in the rat brain.

Alzheimer's disease (AD) is characterized by the extensive deposition of the 42-amino-acid beta-amyloid or A4 protein in neuritic plaques and neurofibrillary tangles within the brain. This protein is liberated from the much larger amyloid protein precursor (APP). Multiple species of APP have been proposed, including several forms that contain a 56 amino acid insert sequence analogous to the Kunitz protease inhibitors. Although expression of APP mRNA is reportedly altered in AD brain and various roles for APP have been proposed, the pathogenesis of amyloid deposition and AD remains unclear. AD is also characterized by specific memory impairments associated with decreased cholinergic activity. While aging rats do not develop mature amyloid pathology, behaviorally impaired aged rats demonstrate an analogous cholinergic decline. In this study, we examined behaviorally characterized aged rats and normal young controls for changes in APP immunohistochemistry by using anti-APP antibodies, which detect N- or C-terminal regions and which distinguish APP species with or without the Kunitz protease inhibitor domain. The results show specific age- and behavior-related changes in cortical APP immunoreactivity as well as limited numbers of APP immunoreactive deposits in the aged rats. Additionally, we found that lesions of the fimbria-fornix pathway, which in part mimic the memory impairments and loss of cholinergic activity seen in AD, result in the marked accumulation of APP immunoreactive material in the region of cholinergic fiber degeneration in the hippocampus. These findings are discussed in relation to the pathogenesis of AD in humans.

Aging↗
PubMed2003

High level of amyloid precursor protein expression in neurite-promoting olfactory ensheathing glia (OEG) and OEG-derived cell lines.

During all the life of a mammal, olfactory ensheathing glia (OEG) permit the entry and navigation of olfactory neuron axons from peripheral to central nervous system (CNS) territory. This physiological characteristic of OEG has been successfully used for promotion of axonal regeneration after CNS injury in animal models. However, cellular and molecular properties responsible for OEG regenerative ability remain to be unveiled. Two approaches may be followed: to carry out genomic or proteomic analysis to detect secreted and/or membrane bound molecules or to examine the expression of molecules previously described as neuritogenic. This is the case of amyloid precursor protein (APP), a neurite-promoting molecule. We have studied the expression of APP by OEG and OEG-derived clonal lines, immortalised with the large T antigen of SV40 (TEG lines). OEG express high levels of APP in vivo and in culture. TEG lines maintained high expression of APP. Western blot analysis showed the presence of high molecular weight forms of APP in OEG, corresponding probably to glycosylated forms and/or to higher expression of the full length APPs. The main APP isoforms present in OEG cultures were APP770 and 751. L-APP isoforms without the exon 15, which are those corresponding with proteoglycan forms, are predominant in glial cells. Our data showed that OEG had three times as much L-APP as astrocytes, which may correlate with OEG neuritogenic capacity. In conclusion APP, a neurite-promoting molecule, is produced by OEG. Its nexin activity, dependent on the Kunitz family of serine protease inhibitors (KPI) domain and/or in combination with its glycosylation level might contribute with other factors to the ability of these cells to foster axonal elongation.

Amyloid beta-Protein Precursor↗
PubMed2004

Progressive cognitive impairment and anxiety induction in the absence of plaque deposition in C57BL/6 inbred mice expressing transgenic amyloid precursor protein.

Numerous transgenic mouse models for Alzheimer's disease (AD) have been generated to recapitulate the histological pathogenesis and behavioral phenotypes of AD brain. However, none of the existing models exhibits the full spectrum of AD symptoms, nor have all of the traits mimicked by the developed animal models been successfully represented within a single mouse line, indicating that the development of transgenic lines showing new features of the AD-like brain should be explored. Here we report on a transgenic mouse line, named Tg-APP (Sw, V717F)/B6, that expresses the human amyloid precursor protein (APP) containing the Swedish and the V717F Indiana mutations in the brains of inbred C57BL/6 mice, designed to eliminate the potential phenotypic variations attributed to the compound genetic backgrounds adopted in most AD mouse models. The Tg-APP (Sw, V717F)/B6 mice expressed the transgene transcript, in the heterozygote state, at a level of 2.6 +/- 0.1 fold higher than that of endogenous mouse APP. However, no Abeta-plaque deposition was produced in the brain of the Tg-APP (Sw, V717F)/B6 mice up to 18 months of age. The Tg-APP(Sw, V717F)/B6 mice at 13-15 months showed reduced expression of calbindin and c-Fos in the brain. The Tg-APP (Sw, V717F)/B6 mice at 11-14 months displayed decreased motor coordination, learning and memory deficits, and severely increased anxiety. These phenotypes were not observed in the Tg-APP (Sw, V717F)/B6 mice at 5-7 months. Microarray analysis revealed altered expression, in the amygdala of the Tg-APP (Sw, V717F)/B6 mice, of genes previously implicated in anxiety. Taken together, these results suggest that the transgenic APP, or its derivatives, produces the age-dependent pathophysiology of the AD-like brain and that the progressive cognitive impairment and anxiety induction can proceed in the absence of visible Abeta-plaque deposition.

Alzheimer Disease↗
PubMed1992

Evidence for intracellular cleavage of the Alzheimer's amyloid precursor in PC12 cells.

The Alzheimer's amyloid precursor (APP) is cleaved by an unidentified enzyme (APP secretase) to produce soluble APP. Fractionation of PC12 cell homogenates in a detergent-free buffer showed the presence of the Kunitz protease inhibitor (KPI)-containing soluble APP (nexin II) in the particulate fraction. Digitonin or sodium carbonate treatment of this fraction solubilized nexin II suggesting that it is contained in the lumen of vesicles. Nexin II production was not affected by lysosomotropic agents, suggesting that APP secretase is not a lysosomal enzyme. Labelling of cell surface proteins by iodination failed to detect full-length APP on the surface of PC12 cells, suggesting that most of this protein is located intracellularly. Furthermore, pulse-chase experiments showed that nexin II is detected in cell extracts before it appears in the culture medium. Cellular nexin II was detected at zero time of chase after only 5 min of pulse labelling with 35S-sulfate, indicated that APP secretase cleavage takes place immediately after APP is sulfated. Temperature block, pulse-chase, and 35S-sulfate-labelling experiments suggested that APP is cleaved by APP secretase intracellularly in the trans-Golgi network (TGN) or in a post-Golgi compartment.

Amyloid beta-Protein Precursor↗
PubMed1997

Assessment of possible protective roles of selenium, zinc, and cis-stilbene oxide against acute T-2 toxin poisoning: a preliminary report.

The efficacy of two free radical scavengers, selenium and zinc, and a microsomal epoxide hydrolase-inducing agent, cis-stilbene oxide on the acute toxicity of T-2 toxin, a potent cytotoxic trichothecene, was investigated. Mice were pretreated daily for 3 consecutive days with either zinc sulfate (4.4 mg/kg, intraperitoneally [i.p.]), sodium selenite (1, 2, and 3 mg/kg i.p.) or cis-stilbene oxide (50 mg/kg i.p.). A full 24-hr after the final dosing with these agents, mice were given T-2 toxin (2, 2.5, or 3 mg/kg i.p.). The acute lethal toxicity of T-2 toxin (2.5 mg/kg) was reduced by administration of only sodium selenite (3 mg/kg) and cis-stilbene oxide (50 mg/kg). No significant effect on weight gain was observed.

Animals↗
PubMed1993

The influence of amino acid sequence on the fibrillogenicity and amyloidogenicity of the carboxy-terminus of beta-amyloid precursor protein.

C-APP, a synthetic peptide corresponding to the C-terminal 20 amino acids of beta-amyloid precursor protein, forms amyloid fibrils in vitro. We investigated the effect of altering the C-APP sequence or deleting part of it on its ability to form amyloid fibrils. Substituting any single amino acid in the C-APP sequence with alanine did not prevent the formation of CAPP-like fibrils. Peptides with single or multiple substitutions that included T11, F14, F15, or Q19 showed reduced fibril-forming capacity while those with K1 and/or K13 replaced with alanine or glutamic acid showed enhanced capacity. When P10 or F14 was replaced with alanine, the fibrils were less congophilic than C-APP fibrils. All of the truncated peptides that were able to form fibrils contained at least 9 amino acids from the N-terminus of C-APP or amino acids 7-20 from the C-terminus. However, several peptides that met these criteria, but started at Q3 or contained only 2-4 amino acids C-terminal to P-10, failed to form many or typical fibrils. Peptides that contained the C-APP sequence plus 5-20 adjacent amino acids from the beta-amyloid precursor protein formed fibrils less readily than C-APP and most of the fibrils were not congophilic. The exception was CAPP-30, which formed moderate amounts of congophilic fibrils resembling C-APP fibrils morphologically. Therefore, proteolysis which releases C-APP from these peptides (except CAPP-30) would be predicted to enhance their amyloidogenicity. These results suggest that several features of C-APP peptide may be important in fibril formation. One of these features is the length of the peptide, with lengths of about 10, 20, or 30 amino acids, favoring fibril formation.

Actin Cytoskeleton↗
PubMed1996

The role of glycosylation in synthesis and secretion of beta-amyloid precursor protein by Chinese hamster ovary cells.

Alzheimer's disease is characterized by beta-amyloid deposition in the brain. This peptide is derived by proteolytic cleavage from beta-amyloid precursor protein (APP), a highly glycosylated membrane glycoprotein containing both N- and O-glycans. There are three major isoforms of APP, which are derived by alternative splicing and contain 695, 751, or 770 amino acids. Since glycosylation can affect many properties of glycoproteins, we studied the role of N- and O-glycosylation in the synthesis and secretion of APP. APP expression was examined in untransfected wild-type, Lec-8 mutant, and ldlD mutant Chinese hamster ovary (CHO) cells and in analogous clonal cell lines expressing either the transfected human wild-type 695-amino-acid form of APP (APP695-WT) or a form mutated to delete N-glycosylation sites (APP695-XX). These studies showed that maturation of APP in CHO cells is accompanied by the addition of multiple short O-glycans with the following structures: Neu5Acalpha2-3Galbeta1-3GalNAc, Neu5Acalpha2-3Galbeta1-3[Neu5Acalpha2-6]GalNAc, and GalNAc. Using glycosylation-defective mutant CHO cell lines and soluble inhibitors of glycosylation, we found that APP secretion was diminished when core N-glycosylation or N-glycan processing was blocked. Surprisingly, similar results were found when synthesis and secretion of either APP695-WT or APP695-XX were analyzed. These results indicate that defective N-glycosylation of other cellular proteins, but not of APP itself, affects the metabolism of APP. Interestingly, inhibition of O-glycosylation did not affect the biosynthesis or secretion of APP. The results of these studies may shed some light on the role that protein glycosylation may play in the pathogenesis of Alzheimer's disease.

Amyloid beta-Protein Precursor↗
PubMed1995

Expression of the amyloid precursor protein of Alzheimer's disease on the surface of transfected HeLa cells.

The principal component of the amyloid which accumulates in Alzheimer's Disease brain is a 4-kDa beta A4 fragment of the amyloid precursor protein (APP). Although APP has the structural features of an integral transmembrane receptor, there has been limited evidence for expression of APP at the plasma membrane. The function of APP and related molecules is unknown. Using rabbit antisera to purified human brain APP, surface labeling of APP is demonstrable in HeLa cells transfected with the APP695 isoform. Indirect immunofluorescence indicates the presence of APP at the surface of unfixed or aldehyde-fixed cells; preembedding immunoelectron microscopy using 5- or 1-nm gold particles and silver enhancement confirms plasma membrane labeling as well as labeling within intracellular membrane vesicles. Immunolabeling of unfixed cells at 4 degrees C followed by incubation at 37 degrees C shows APP within endocytic vesicles. Transfected HeLa cells with prominent surface APP were larger with more extensive microvilli than nonimmunoreactive HeLa cells. This is consistent with the postulated role of APP as a mediator of cell surface adhesion and membrane-matrix stabilization.

Alzheimer Disease↗
PubMed2002

A role for presenilin 1 in regulating the delivery of amyloid precursor protein to the cell surface.

Presenilin 1 (PS1) and presenilin 2 play a critical role in the gamma-secretase processing of amyloid precursor protein (APP) and Notch1. Here, we investigate maturation and intracellular trafficking of APP and other membrane proteins in cells expressing an experimental PS1 deletion mutant (deltaM1,2). Stable expression of deltaM1,2 impairs gamma-secretase processing of Notch1 and delays Abeta secretion. Kinetic studies show enhanced O-glycosylation and sialylation of holo-APP and marked accumulation of APP COOH-terminal fragments (CTFs). Surface biotinylation, live staining, and trafficking studies show increased surface accumulation of holo-APP and CTFs in deltaM1,2 cells resulting from enhanced surface delivery of newly synthesized APP. Expression of a loss-of-function PS1 mutant (D385A) or incubation of cells with gamma-secretase inhibitors also increases surface levels of holo-APP and CTFs. In contrast to APP, glycosylation and surface accumulation of another type I membrane protein, nicastrin, are markedly reduced in deltaM1,2 cells. Finally, expression of deltaM1,2 results in the increased assembly and surface expression of nicotinic acetylcholine receptors, illustrating that PS1's influence on protein trafficking extends beyond APP and other type I membrane protein substrates of gamma-secretase. Collectively, our findings provide evidence that PS1 regulates the glycosylation and intracellular trafficking of APP and select membrane proteins.

Amyloid Precursor Protein Secretases↗
PubMed1994

Effect of ionophores on the processing of the beta-amyloid precursor protein in different cell lines.

1. Alzheimer's disease is characterized by the deposition in the brain of extracellular amyloid plaques and vascular deposits consisting mostly of amyloid beta-peptide (A beta). A beta, a polypeptide of 39-43 amino acids (M(r), approximately 4 kDa), is derived proteolytically from a family of proteins of 695-770 amino acids (M(r), approximately 110-140 kDa) called beta-amyloid precursor protein (beta APP). 2. beta APP, an integral membrane glycoprotein, is extensively posttranslationally modified within the endoplasmic reticulum (ER) and various Golgi compartments. beta APP is cleaved by proteases in either the trans-Golgi network or the post-Golgi apparatus and then secreted as a truncated soluble form into the conditioned media of cultured cells and cerebrospinal fluid samples from human subjects. beta APP can be processed either by an antiamyloidogenic secretory pathway or by an endosomal/lysosomal pathway. 3. I studied the effect of two ionophores on the processing of beta APP in cultured cells. Monensin and, in some cases, ammonium chloride increase the intracellular accumulation of beta APP in several cell lines and may alter its processing. Monensin, which had the most consistent effects, also inhibited secretion of beta APP in a differentiated (growth factor mediated) cell line. Nigericin, with greater K+ selectivity, was less able to alter the accumulation and possible processing of the protein. 4. These results suggest that the increase in the accumulation of intracellular beta APP observed after treating cells with ionophores has some specificity. The selective effect of these ionophores on the metabolism of beta APP may provide a model system to analyze the pathways for studying maturation, secretion, and degradation of beta APP.

Ammonium Chloride↗
PubMed1996

Differential effect of tacrine and physostigmine on the secretion of the beta-amyloid precursor protein in cell lines.

The senile plaque in Alzheimer's disease (AD) consists mainly of the amyloid beta-peptide (A beta) derived from a family of large integral membrane glycoproteins, beta-amyloid precursor proteins (beta APP). Soluble derivatives of beta APP generated by the proteolytic processing of full-length beta APP are normally secreted into the conditioned medium of cultured cells. Here we have investigated the possibility that the processing of beta APP can be regulated by the cholinesterase inhibitors physostigmine and tacrine. Both drugs mildly improve cognitive functions in some patients with AD. We analyzed the level of beta APP in glial, neuroblastoma, and pheochromocytoma cells by immunoblotting cell lysates and conditioned media using a monoclonal antibody, MAb22C11. The levels of soluble beta APP derivatives normally present in conditioned media were severely inhibited by treating cells with tacrine but not with physostigmine. Whereas the treatment of cells with tacrine resulted in a small decrease in the intracellular levels of beta APP, treating cells with physostigmine resulted in a slight increase in the intracellular levels of beta APP compared to untreated cells. The effect of tacrine on the secretion of beta APP was not affected by cotreating cells with muscarinic agents, staurosporine, or the calcium ionophore. Our results suggest that a decrease in the secretion of beta APP by tacrine did not depend on its anticholinesterase activity and that tacrine operates via a noncholinergic mechanism.

Amyloid beta-Protein Precursor↗
PubMed1999

Kinetics and characteristics of an acute phase response following cardiac arrest.

OBJECTIVE: Inflammation and hypoxia are frequently associated, but their interaction is poorly understood. In vitro studies have shown that hypoxia stimulates the genes of acute phase proteins (APP) and cytokines known to induce APP. We decided to determine kinetics and potential determinants of an acute phase response after cardiac arrest and to assess whether isolated moderate hypoxia can induce APP in humans in vivo. DESIGN: Prospective, observational study in patients and human experiment. SETTING: Tertiary care university hospital. PATIENTS AND PARTICIPANTS: 22 patients after primarily successful cardiopulmonary resuscitation (CPR) and 7 healthy volunteers. INTERVENTIONS: None in patients; exposure of volunteers to simulated altitude (460 torr/6 h). RESULTS: Following CPR, type-1 APP (C-reactive protein, alpha 1-acidglycoprotein, serum amyloid A) and type-2 APP (haptoglobin, alpha 1-antitrypsin) increased consistently within 1-2 days and the 'negative' APP transferrin was downregulated. This APP response occurred irrespective of the cause of arrest, the estimated time of anoxia, clinical course or patient outcome and was not different in patients with and without infectious complications. Exposure of healthy volunteers to less severe but more prolonged hypoxia did not induce APP, although a time dependent increase of serum erythropoietin (EPO) was measurable under these conditions, indicating the activation of oxygen dependent gene expression. CONCLUSIONS: (i) A marked acute phase response occurs regularly after cardiac arrest, but within the complexity of this situation the severity of hypoxia is not a predominant determinant of this response. (ii) Despite in vitro evidence for similarities in the oxygen dependent regulation of APP and EPO production, the oxygen sensitivity of these proteins in vivo is different. (iii) Measurements of APP are not revealing regarding infectious complications in the early phase after CPR.

Acute-Phase Proteins↗
PubMed2005

Gender differences in trabecular bone architecture of the distal radius assessed with magnetic resonance imaging and implications for mechanical competence.

High-resolution magnetic resonance imaging (hrMRI) has recently made it possible to evaluate trabecular bone structure in vivo. Despite obvious gender differences in fracture incidence at the distal radius, little is known about gender differences in trabecular bone microarchitecture and its relationship to the structural strength of the forearm. The aim of this study was to determine trabecular bone structure in the distal radius of elderly women and men and its correlation with failure loads of the distal radius as determined in a fall configuration. Specifically, we tested the hypotheses that structural indices differ between women and men and that they offer information that is independent from BMD for predicting structural strength. Intact right arms were obtained from 73 formalin-fixed cadavers (age 80+/-11 years, 43 women, 30 men). Trabecular structural indices (apparent bone volume fraction [app. BV/TV], trabecular number [app. Tb.N], trabecular separation [app. Tb.Sp], trabecular thickness [app. Tb.Th] and fractal dimension [Frac.Dim]) were assessed in the distal metaphysis, using hrMRI with 156 microm in-plane resolution and proprietary digital image analysis, while BMD was measured with dual X-ray absorptiometry (DXA). Women displayed significantly lower BMD (-29.8%, p <0.001), app. BV/TV (-8.2%, p <0.05) and app. Tb.Th (-10.2%, p <0.001) than men, whereas app. Tb.N, app. Tb.Sp. and fractal dimension did not differ significantly. Structural parameters differed between normal and osteopenic women (BV/TV: -11%, p <0.01; Tb.Th: -8%, p <0.001) and between normal and osteoporotic women BV/TV: -21%, p <0.001; Tb.Th: -16%, p <0.001). App. BV/TV, app. Tb.Th and fractal dimension provided information independent from BMD in the prediction of radial failure loads in multiple regression models. These findings imply that it should be of clinical interest to monitor both bone mass and trabecular microstructure for predicting osteoporotic fracture risk.

Absorptiometry, Photon↗
PubMed2005

Quantification of trabecular bone structure using magnetic resonance imaging at 3 Tesla--calibration studies using microcomputed tomography as a standard of reference.

The purpose of this study is to use high-resolution magnetic resonance (MR) imaging at 3 Tesla (3T) to quantify trabecular bone structure in vitro using femoral head specimens, and to correlate the calculated structure measures with those that were determined using microcomputed tomography (microCT), the standard of reference. Fifteen cylindrical cores were obtained from fresh femoral heads after total hip arthroplasty. MR images were obtained at 3T using a transmit-receive wrist coil. High-resolution coronal images were acquired using a modified three-dimensional (3D) fast-gradient echo sequence. From these data sets two-dimensional (2D) structural parameters analogous to bone histomorphometry were derived by using both mean intercept length (MIL) methods based on the plate model and the more recent model-assumption free 3D distance-transformation (DT) methods. The parameters measured by the 2D plate model-based MIL method and the DT method included apparent (App). BV/TV (bone volume/total volume), App. Tb.Th (trabecular thickness), App. Tb.Sp (trabecular separation), and App. Tb.N (trabecular number). Identical regions of interest were analyzed in the MR images and the microCT data sets, and similar structure measures were derived. The means and standard deviations of the parameters over all slices were calculated and MR-derived measures were correlated with those derived from the microCT data sets using linear regression analyses. Structure measures were overestimated with MRI, for example, the mean App. BV/TV was 0.45 for MRI and 0.20 for microT, and the slope of the graph was 1.45. App. Tb.Th was overestimated by a factor of 1.9, whereas App. Tb.Sp was underestimated; Tb.N showed the smallest effect. Correlations between the individual parameters were excellent (App. BV/TV, r2 = 0.82; App. Tb.Sp, r2 = 0.84; App. Tb.N, r2 = 0.81), except for App.Tb.Th (r2 = 0.67). The results of this study show that trabecular bone structure measures may be obtained using 3T MR imaging. These measures, although higher than the standard of reference, show a highly significant correlation with true structure measures obtained by microCT.

Aged↗