Biomedical subjects

J Tian

Publications and source records attributed to J Tian.

At least 19 recordsLinked to original sources

PubMed2007

The postnatal maternal environment influences diabetes development in nonobese diabetic mice.

When nonobese-diabetic (NOD) mouse embryos were implanted into pseudopregnant mothers of a nonautoimmune mouse strain, the progeny had a reduced type 1 diabetes (T1D) incidence, suggesting that transmission of maternal autoantibodies is important for T1D development. Whether eliminating islet autoantibody transmission in utero, or postnatally (through milk), prevented T1D is unknown. Herein, we show that fostering newborn NOD mice on B-cell deficient NOD.Igmu-/- dams does not prevent T1D, demonstrating that postnatally transmitted islet autoantibodies are not required for disease pathogenesis. Additionally, NOD.Igmu-/- mice reared on NOD dams did not develop T1D, indicating that autoantibody transmission to B-cell deficient NOD neonates is insufficient to trigger T1D. Interestingly, newborn NOD mice that were reared by ICR (but not NOD or C57BL/6) dams had reduced T1D incidence, although not as reduced as that reported after embryo transfer to ICR mice, suggesting that both prenatal and postnatal factors contribute to the observed reduction in T1D incidence. Thus, NOD mice have different risks for developing T1D depending on the strain of their foster mother, and both prenatal and postnatal maternal factors, other than islet autoantibodies, influence their T1D incidence. The results may be relevant for understanding the increasing incidence of T1D and designing interventions.

Animals↗

PubMed2006

Prevalence of abnormal serum vitamin D, PTH, calcium, and phosphorus in patients with chronic kidney disease: results of the study to evaluate early kidney disease.

Abnormalities of mineral metabolism occur early in chronic kidney disease. Quantification of the prevalence of these abnormalities has not been described using current assays nor in large unselected populations. This outpatient cohort cross-sectional study was conducted in 153 centers, (71% primary care practices). Blood for parathyroid hormone (PTH), vitamin D metabolites, creatinine, calcium (Ca), and phosphorus (P) were drawn between June and October 2004. Low 1,25-dihydroxyvitamin D (1,25 OH2 D3) was defined as <22 pg/ml. The 1814 patients had a mean age of 71.1 years old; 48% had diabetes mellitus (DM). Low 1,25 OH2 D3 was evident at all estimated glomerular filtration rate (eGFR) levels: 13% in those with eGFR >80 ml/min, >60% in those with eGFR <30 ml/min. High PTH (>65pm/dl) occurred in 12% with eGFR >80 ml/min. Serum Ca and P were normal until eGFR was <40 ml/min. Significant differences in the mean and median values of 1,25 OH2 D3, PTH, but not 25(OH)D3 levels, were seen across deciles of eGFR (P<0.001). Multivariate analysis revealed that DM, increased urinary albumin/creatinine ratio and lower eGFR predicted lower values of 1,25 OH2 D3. A high prevalence of mineral metabolite abnormalities occurs in a large unreferred US cohort. Low 1,25 OH2 D3 and elevated PTH are common at higher eGFR than previously described. As bone, cardiovascular disease, and mineral metabolite are correlated; further studies are necessary to determine the importance of these findings relative to outcomes.

Aged↗

PubMed2006

Inhibition of hepatocarcinoma by systemic delivery of Apoptin gene via the hepatic asialoglycoprotein receptor.

Specificity is a prerequisite for systemic gene therapy of hepatocarcinoma. In vitro, the tumor-specific viral death effector Apoptin selectively induces apoptosis in malignant hepatic cells. Intratumoral treatment of xenografted subcutaneous hepatomas with Apoptin results in tumor regression. Here, we report a systemic delivery vehicle containing the Apoptin gene linked to asialoglycoprotein (Asor), which targets asialoglycoprotein receptor (ASGPR) present only on the surface of hepatocytes. In vitro, the protein-DNA complex Asor-Apoptin induced apoptosis in HepG2 hepatocarcinoma cells but not in normal L-02 hepatocytes. Non-hepatocyte-derived tumorigenic human A549 cells lacking the membrane ASGPR were not affected by Asor-Apoptin. In vivo systemic delivery of Asor-Apoptin via the tail vein into mice bearing in situ hepatocarcinoma resulted in specific and efficient distribution of Apoptin in both hepatocarcinoma cells and normal hepatocytes. Five days after injection of Asor-Apoptin, the in situ hepatocarcinomas showed significant signs of regression, whereas the surrounding normal hepatocytes did not. Systemically delivered Asor-LacZ expressing non-apoptotic LacZ gene did not inhibit tumor growth. Our data reveal that systemic delivery of Asor-Apoptin specifically induces apoptosis in malignant hepatocytes and thus constitutes a powerful and safe therapeutics against hepatocarcinomas.

Animals↗

PubMed2006

Cloning and molecular characterization of three novel LMW-i glutenin subunit genes from cultivated einkorn (Triticum monococcum L.).

Three novel low molecular weight (LMW) glutenin subunits from cultivated einkorn (Triticum monococcum L., A(m)A(m), 2n = 2x = 14) were characterized by SDS-PAGE and molecular weights determined by MALDI-TOF-MS. Their coding genes were amplified and cloned with designed AS-PCR primers, revealing three complete gene sequences. All comprised upstream, open reading frame (ORF), downstream and no introns were present. The deduced amino acid sequences showed that all three genes, named as LMW-M1, LMW-M3 and LMW-M5, respectively, belonged to the LMW-i type subunits with the predicted molecular weight between 38.5206 and 38.7028 kDa. They showed high similarity with other LMW-i type genes from hexaploid bread wheats, but also displayed unique features. Particularly, LMW-M5 subunit contained an extra cysteine residue in the C-terminus except for eight conserved cysteines, which resulted from a single-nucleotide polymorphism (SNP) of the T-C transition, namely arginine --> cysteine substitution at position 242 from the N-terminal end. This is the first report that the LMW-i subunit contained nine cysteines residues that could result in a more highly cross-linked and more elastic glutenin suggesting that LMW-M5 gene may associates with good quality properties. In addition, a total of 25 SNPs and one insertions/deletions (InDels) were detected among three LMW-i genes, which could result in significant functional changes in polymer formation of gluten. It is anticipated that these SNPs could be used as reliable genetic markers during wheat quality improvement. The phylogenetic analysis indicated that LMW-i type genes apparently differed from LMW-m and LMW-s type genes and diverged early from the primitive LMW-GS gene family, at about 12.92 million years ago (MYA) while the differentiation of A(m) and A genomes was estimated at 3.98 MYA.

Amino Acid Sequence↗

PubMed2006

Adipogenic human adenovirus-36 reduces leptin expression and secretion and increases glucose uptake by fat cells.

OBJECTIVE: Human adenovirus Ad-36 causes adiposity in animal models and enhances differentiation and lipid accumulation in human and 3T3-L1 preadipocytes, which may, in part, explain the adipogenic effect of Ad-36. We determined the consequences of Ad-36 infection on leptin and glucose metabolism in fat cells. DESIGN: 3T3-L1 preadipocytes were used to determine the effect of infection by human adenoviruses Ad-36, Ad-2, Ad-9 and Ad-37 on leptin secretion and lipid accumulation. Rat primary adipocytes were used to determine the effect of Ad-36 infection on leptin secretion and glucose uptake in vitro. Furthermore, the effect of Ad-36 on expressions of leptin and selected genes of de novo lipogenesis pathway of visceral adipose tissue were compared ex vivo, between Ad-36 infected and uninfected control rats. RESULTS: Ad-36 suppressed the expression of leptin mRNA in 3T3-L1 cells by approximately 58 and 52% on days 3 and 5 post-infection, respectively. Leptin release normalized to cellular lipid content was 51% lower (P<0.002) in the Ad-36 infected 3T3-L1 cells. Lipid accumulation was significantly greater and leptin secretion was lower for the 3T3-L1 cells infected with other human adenoviruses Ad-9, Ad-36, or Ad-37. Whereas, human adenovirus Ad-2 did not influence cellular lipid accumulation or the leptin release. In rat primary adipocytes, Ad-36 reduced leptin release by about 40% in presence of 0.48 (P<0.01) or 1.6 nM insulin (P<0.05) and increased glucose uptake by 93% (P<0.001) or 18% (P<0.05) in presence of 0 or 0.48 nM insulin, respectively. Next, the adipose tissue of Ad-36 infected rats showed two to fivefold lower leptin mRNA expression, and 1.6- to 21-fold greater expressions for acetyl Co-A carboxylase-1 and 1.2- to 6.3-fold greater expressions for fatty acid synthase, key genes of de novo lipogenesis, compared to the uninfected weight and adiposity matched controls. CONCLUSION: The in vitro and ex vivo studies show that Ad-36 modulates adipocyte differentiation, leptin production and glucose metabolism. Whether such a modulation contributes to enhanced adipogenesis and consequent adiposity in Ad-36 infected animals or humans needs to be determined.

3T3-L1 Cells↗

PubMed2006

Relationships in Alzheimer's disease between the extent of Abeta deposition in cerebral blood vessel walls, as cerebral amyloid angiopathy, and the amount of cerebrovascular smooth muscle cells and collagen.

The relationship between degree of cerebral amyloid angiopathy (CAA) and the amount of smooth muscle cells (SMCs) and deposition of collagen IV fibres (COL IV) was investigated in the frontal and occipital cortex of 70 patients with autopsy confirmed Alzheimer's disease (AD). The extent of CAA was significantly greater in occipital than in frontal cortex, although SMC loss was greater in frontal than in occipital cortex. COL IV staining was significantly higher in occipital than in frontal cortex. The degree of SMC loss correlated with CAA, as Abeta40 but not as Abeta42 or total Abeta, in frontal cortex, but not in occipital cortex. Leptomeningeal arteries within occipital cortex showed significantly greater external diameter, greater wall thickness and greater luminal area than those in frontal cortex. The degree of CAA correlated with thickness of blood vessel wall and external diameter in frontal cortex, whereas extent of SMC loss correlated with thickness of blood vessel wall in occipital cortex. There were significant negative correlations between duration of disease and thickness of vessel wall, external diameter and luminal area. In patients with disease durations exceeding 10 years, external vessel diameter and thickness of the vessel wall were both halved compared with patients with durations less than 5 years; luminal area was reduced by about 75%. Blood vessels in AD undergo degenerative changes involving deposition of Abeta and COL IV with loss of SMC. SMC loss may relate to increasing Abeta deposition in early stages of disease, but this relationship may be lost with disease progression.

Aged↗

PubMed2006

Comparison of extent of tau pathology in patients with frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), frontotemporal lobar degeneration with Pick bodies and early onset Alzheimer's disease.

In order to gain insight into the pathogenesis of frontotemporal lobar degeneration (FTLD), the mean tau load in frontal cortex was compared in 34 patients with frontotemporal dementia linked to chromosome 17 (FTDP-17) with 12 different mutations in the tau gene (MAPT), 11 patients with sporadic FTLD with Pick bodies and 25 patients with early onset Alzheimer's disease (EOAD). Tau load was determined, as percentage of tissue occupied by stained product, by image analysis of immunohistochemically stained sections using the phospho-dependent antibodies AT8, AT100 and AT180. With AT8 and AT180 antibodies, the amount of tau was significantly (P < 0.001 in each instance) less than that in EOAD for both FTDP-17 (8.5% and 10.0% respectively) and sporadic FTLD with Pick bodies (16.1% and 10.0% respectively). With AT100, the amount of tau detected in FTDP-17 was 54% (P < 0.001) of that detected in EOAD, but no tau was detected in sporadic FTLD with Pick bodies using this particular antibody. The amount of insoluble tau deposited within the brain in FTDP-17 did not depend in any systematic way upon where the MAPT mutation was topographically located within the gene, or on the physiological or structural change generated by the mutation, regardless of which anti-tau antibody was used. Not only does the amount of tau deposited in the brain differ between the three disorders, but the pattern of phosphorylation of tau also varies according to disease. These findings raise important questions relating to the role of aggregated tau in neurodegeneration - whether this represents an adaptive response which promotes the survival of neurones, or whether it is a detrimental change that directly, or indirectly, brings about the demize of the affected cell.

Adult↗

PubMed2006

Genetic associations between cathepsin D exon 2 C-->T polymorphism and Alzheimer's disease, and pathological correlations with genotype.

Genetic variations represent major risk factors for Alzheimer's disease (AD). While familial early onset AD is associated with mutations in the amyloid precursor protein and presenilin genes, only the e4 allele of the apolipoprotein E (APOE) gene has so far been established as a genetic risk factor for late onset familial and sporadic AD. It has been suggested that the C-->T (224Ala-->Val) transition within exon 2 of the cathepsin D gene (CTSD) might represent a risk factor for late onset AD. The objective of this study was to investigate whether possession of the CTSD exon 2 T allele increases the risk of developing AD, and to determine whether this modulates the amyloid pathology of the disease in conjunction with, or independent of, the APOE e4 allele. Blood samples were obtained from 412 patients with possible or probable AD and brain tissues from a further 148 patients with AD confirmed by postmortem examination. CTSD and APOE genotyping were performed by PCR on DNA extracted from blood, or from frontal cortex or cerebellum in the postmortem cases. Pathological measures of amyloid beta protein (Abeta), as plaque Abeta40 and Abeta42(3) load and degree of cerebral amyloid angiopathy were made by image analysis or semiquantitative rating, respectively. CTSD genotype frequencies in AD were not significantly different from those in control subjects, nor did these differ between cases of early or late onset AD or between younger and older controls. There was no gene interaction between the CTSD T and APOE e4 alleles. The amount of plaque Abeta40 was greater in patients carrying the CTSD T allele than in non-carriers, and in patients bearing APOE e4 allele compared with non-carriers. Possession of both these alleles acted synergistically to increase levels of plaque Abeta40, especially in those individuals who were homozygous for the APOE e4 allele. Possession of the CTSD T allele had no effect on plaque Abeta42(3) load or degree of CAA. Possession of the CTSD T allele does not increase the risk of developing AD per se, but has a modulating effect on the pathogenesis of the disorder by increasing, in concert with the APOE e4 allele, the amount of Abeta deposited as senile plaques in the brain in the form of Abeta40.

Aged↗

PubMed2005

Influence of hydroxyethyl starch on lipopolysaccharide-induced tissue nuclear factor kappa B activation and systemic TNF-alpha expression.

BACKGROUND: Several studies have shown beneficial effects of hydroxyethyl starch (HES) on organ damage in the treatment of severe inflammatory situations, but the mechanisms remain unclear. Nuclear factor-kappa B (NF-kappaB) activation is known to contribute to many aspects of inflammatory injury and organ dysfunction in critical illness, and tumor necrosis factor-alpha (TNF-alpha) is considered the most important pro-inflammatory cytokine. The present study was undertaken to test whether HES (200/0.5) has some effects on tissue NF-kappaB activity and systemic TNF-alpha expression induced by lipopolysaccharide in order to define a possible mechanism of the beneficial effects of HES. METHODS: Male Wistar rats were randomly divided into seven groups treated with saline, lipopolysaccharide (LPS, 6 mg/kg), LPS plus HES (3.75, 7.5, 15, 30 ml/kg), or HES (30 ml/kg) alone. Two hours after LPS challenge, NF-kappaB activation in the lungs, hearts, livers, and kidneys were examined with an electrophoretic mobility shift assay. Four hours after LPS challenge, plasma TNF-alpha concentrations were measured using an enzyme-linked immunosorbance assay. RESULTS: 3.75 and 7.5 ml/kg HES suppressed LPS-induced NF-kappaB activation in the four tissues and decreased plasma TNF-alpha elevation. The effects of 15 ml/kg HES was only significant in inhibiting NF-kappaB activity in the lung and liver. No effect of 30 ml/kg HES was revealed in all the cases. CONCLUSION: Lower doses of HES may inhibit tissue NF-kappaB activation and systemic TNF-alpha elevation after LPS challenge, which might be helpful during sepsis.

Animals↗

PubMed2005

The expression of native and cultured human retinal pigment epithelial cells grown in different culture conditions.

AIM: To determine the transcriptional proximity of retinal pigment epithelium (RPE) cells grown under different culture conditions and native RPE. METHODS: ARPE-19 cells were grown under five conditions in 10% CO(2): "subconfluent" in DMEM/F12+10% FBS, "confluent" in serum and serum withdrawn, and "differentiated" for 2.5 months in serum and serum withdrawn medium. Native RPE was laser microdissected. Total RNA was extracted, reverse transcribed, and radiolabelled probes were hybridised to an array containing 5,353 genes. Arrays were evaluated by hierarchical cluster analysis and significance analysis of microarrays. RESULTS: 78% of genes were expressed by native RPE while 45.3--47.7% were expressed by ARPE-19 cells, depending on culture condition. While the most abundant genes were expressed by native and cultured cells, significant differences in low abundance genes were seen. Hierarchical cluster analysis showed that confluent and differentiated, serum withdrawn cultures clustered closest to native RPE, and that serum segregated cultured cells from native RPE. The number of differentially expressed genes and their function, and profile of expressed and unexpressed genes, demonstrate differences between native and cultured cells. CONCLUSIONS: While ARPE-19 cells have significant value for studying RPE behaviour, investigators must be aware of how culture conditions can influence the mRNA phenotype of the cell.

Aged↗

PubMed2005

Is there a relation between APOE expression and brain amyloid load in Alzheimer's disease?

BACKGROUND: It has been proposed that, independent of the epsilon4 allele, APOE promoter polymorphisms (-491 A/T and -219 G/T) may be risks factor for Alzheimer's disease by modulating APOE expression. OBJECTIVE: To measure the level of APOE expression in Alzheimer's disease. METHODS: Brains were obtained at necropsy from 114 patients with early and late onset sporadic Alzheimer's disease in Greater Manchester (UK) during years 1986 to 2001. Total RNA was extracted from 84 brains. Purified lymphocytes were obtained from fresh blood from 16 probable Alzheimer cases from Lille (France). APOE and beta-actin gene expression was determined by reverse transcriptase polymerase chain reaction in brain and lymphocytes. RESULTS: An inverse correlation between APOE expression level and A beta loads was observed. As previously described and extended to 114 cases here, an association between the -219 TT genotype and a higher level of parenchymal A beta deposition was found, irrespective of APOE epsilon4 allele status. This effect was more pronounced in older individuals, whereas higher A beta load appeared more closely related to epsilon4 in the younger age group (cut off point at the median age at death (72.5 years)). The -219 TT genotype was associated with a decrease in APOE expression. There was a 60% decrease in APOE expression in lymphocytes from probable Alzheimer cases v controls (p = 0.01). CONCLUSIONS: In the oldest individuals, reduced APOE expression, modulated in part by -219 G/T polymorphism, may influence risk and constitute a determinant A beta load in Alzheimer's disease.

Actins↗

PubMed2004

A polymorphism in the angiotensin 1-converting enzyme gene is associated with damage to cerebral cortical white matter in Alzheimer's disease.

The impact of the insertion (I)/deletion (D) (I/D) polymorphism in the angiotensin 1-converting enzyme (ACE) gene on the extent of white matter myelin loss (ML) was investigated in four regions of the cerebral cortex in an autopsy-confirmed series of 93 patients with Alzheimer's disease (AD). The possible influence of APO E epsilon4 allele acting in concert with ACE D allele was assessed. The extent of ML did not differ between D/D, I/D and I/I genotype groups when data from all four brain regions were combined. However, separate analysis showed that the frontal and temporal cortex tended to be affected more severely by ML in patients with D/D genotype compared to those with I/D and I/I genotypes. Stratification according to APO E epsilon4 allele revealed a greater overall ML in patients bearing at least one copy of ACE D allele and one APO E epsilon4 allele, especially in individuals homozygous for both. The APO E epsilon4 allele may therefore act synergistically in patients with AD (and other subjects) bearing ACE D/D genotype to increase the risk of ML, perhaps through transient ischaemic episodes consequent upon poor cardiac output associated with coronary atherosclerosis in patients with the APO E epsilon4 allele.

Adult↗

PubMed2004

Efficient high-frequency body coil for high-field MRI.

The use of body coils is favored for homogeneous excitation, and such coils are often paired with surface coils or arrays for sensitive reception in many MRI applications. While the body coil's physical size and resultant electrical length make this circuit difficult to design for any field strength, recent efforts to build efficient body coils for applications at 3T and above have been especially challenging. To meet this challenge, we developed an efficient new transverse electromagnetic (TEM) body coil and demonstrated its use in human studies at field strengths up to 4 T. Head, body, and breast images were acquired within peak power constraints of <8 kW. Bench studies indicate that these body coils are feasible to 8 T. RF shimming was used to remove a high-field-related cardiac imaging artifact in these preliminary studies. P41RR13230

Equipment Design↗

PubMed2004

Unexpected pulmonary uptake of adenovirus vectors in animals with chronic liver disease.

When adenovirus vectors are injected intravenously, most of the virions are quickly taken up by the reticuloendothelial system, primarily by the liver macrophages known as Kupffer cells. However, little is known about the behavior of adenovirus vectors when there is pre-existing liver disease. To study this, we examined the biodistribution of intravenously injected vector in a rat model of cirrhosis induced by bile duct ligation. Using quantitative PCR and fluorescently tagged adenovirus vectors, we observed a significant reduction in vector uptake by the cirrhotic liver and increased accumulation in the lungs. Immunocytochemistry and electron microscopy demonstrated that this was due to changes in the reticuloendothelial system, with the vector being taken up by large numbers of pulmonary intravascular macrophages in the lungs of cirrhotic rats. Interestingly, expression of vector-encoded luciferase was significantly reduced in the livers of cirrhotic rats, but was not increased in the lungs. These data demonstrate that the biodistribution of adenovirus vectors in rats is altered by cirrhosis, which suggests the possibility that these vectors might behave unexpectedly in patients with pre-existing liver conditions, particularly since pulmonary reticuloendothelial changes are known to occur in human disease.

Adenoviridae↗

PubMed2004

Relationships between arteriosclerosis, cerebral amyloid angiopathy and myelin loss from cerebral cortical white matter in Alzheimer's disease.

Pathological relationships between damage to the deep white matter of the cerebral cortex [as evidenced by myelin loss (ML)], cerebral amyloid angiopathy (CAA) and arteriosclerosis (ART) were investigated in the brains of 137 patients with autopsy-confirmed Alzheimer's disease (AD), in order to better understand the causes of white matter damage in AD, and the contribution of this to the pathogenesis of the disorder. All 137 patients had some degree of CAA in one or more brain regions although the occipital cortex was severely affected by CAA more frequently, and consequently mean CAA severity score was significantly greater, than other cortical regions. Eighty-seven patients (63.5%) were affected by ML, with more patients showing ML from occipital cortex than from other cortical regions leading to a significantly higher mean ML severity score in this region. One hundred and twenty-six patients (92%) were affected by ART, although the occipital cortex was not more frequently affected by ART than other cortical areas, the mean ART severity score in occipital cortex was nonetheless significantly greater than that of frontal and temporal cortex. Eighty-seven patients showed both CAA and ML, although there was only a weak correlation between degree of CAA and extent of ML (P = 0.035). Forty-seven patients showed ML and significant ART, 16 patients showed significant ART but no ML, 40 patients showed ML in the absence of significant ART and 34 patients showed neither significant ART nor ML. Overall, and for each of the four brain regions, the extent of ML correlated significantly (P < 0.001) with degree of ART. However, when only those 47 patients with ML and significant ART were considered, much stronger correlations between the extent of ML and the degree of ART were achieved both overall and within each of the four brain regions. The overall ART severity score (and overall scores for each pathological marker of ART) significantly correlated with that of CAA (P < 0.001). Pathological processes leading to white matter damage, in terms of ML at least, in AD are thus likely to be heterogeneous. Many patients suffer ML in association with ART, but in others ML cannot be explained by presence of ART or CAA. In such patients, autoregulatory changes in blood vessels might be responsible for ML. The association between the extent of CAA and ART suggests shared risk factors for each pathological change.

Age of Onset↗

PubMed2004

Association between apolipoprotein E e4 allele and arteriosclerosis, cerebral amyloid angiopathy, and cerebral white matter damage in Alzheimer's disease.

OBJECTIVE: To investigate the association between white matter damage, as evidenced by myelin loss (ML), the extent of cerebral amyloid angiopathy (CAA), or arteriosclerosis (Art), and apolipoprotein E (ApoE) e4 allele in Alzheimer's disease (AD), in order to understand the causes of damage to white matter in AD and its contribution to the pathogenesis of the disorder. MATERIALS AND METHODS: Brain tissues were obtained from 94 patients with AD confirmed by autopsy. ApoE genotyping was performed by PCR on DNA extracted from frontal cortex or cerebellum. CAA and Art were assessed on Weigert's haematoxylin and eosin stained sections in frontal, temporal, parietal, and occipital cortices; the extent of ML was scored on Luxol fast blue stained sections of these regions. RESULTS: The ApoE e4 allele frequency in the 61 patients with ML was not significantly different from that in the 33 patients without ML, nor did this differ in the 84 patients with Art from that in the 10 patients without Art. There were no significant differences in the proportions of patients with genotypes containing 0, 1, or 2 ApoE e4 alleles in the presence or absence of ML or Art. The mean ML, Art, or CAA scores within each region, and the total scores summed across all four brain regions, did not differ between patients with 0, 1, or 2 ApoE e4 alleles. However, the mean ML severity score in the occipital cortex was significantly greater than that in the frontal or temporal cortices in patients with 1 or 2 ApoE e4 alleles. The severity of CAA in the occipital cortex was significantly higher than that in other areas of cortex in patients with 0 or 2 ApoE e4 alleles. The mean Art score in the occipital cortex was greater than that in the temporal cortex in patients with two ApoE e4 alleles and was higher than that in the frontal cortex in patients with one ApoE e4 allele. CONCLUSIONS: The likelihood of patients with AD suffering from CAA, Art, or ML is not influenced by ApoE e4 allele, nor is the overall burden of these pathological changes in the brain. However, the distribution of ML, CAA, and Art within the brain is at least partly influenced by genotype and dosage of ApoE e4 allele, with the occipital cortex being more severely affected by all of these pathological changes in e4 allele bearers, particularly when two ApoE e4 alleles are present.

Aged↗

PubMed2004

Cerebral amyloid angiopathy and dementia.

Cerebral amyloid angiopathy (CAA) is a fundamental part of the pathology of many disorders causing dementia and/or cerebral haemorrhage. In Alzheimer's disease (AD), CAA is due to the deposition of amyloid alpha protein (Abeta) within the adventitia and media of leptomeningeal and brain parenchymal arteries. Although virtually all cases of AD show CAA to a greater or lesser extent, the brain distribution of CAA is not uniform with the occipital lobe being the most commonly and most severely affected region. In vessels affected by CAA, local muscle and elastic elements are lost and replaced by amyloid fibrils, thereby weakening the overall structure of the vessel. Consequently, CAA predisposes towards cerebral infarction and cerebral haemorrhage, though the clinical affects of CAA in AD are mostly silent, or at least are ''masked'' by the greater degree of neuronal dysfunction induced by senile plaque (SP) formation and neurofibrillary degeneration. Nonetheless, major cerebral infarctions with focal neurological deficits can occur in some cases of AD, and CAA is a major cause of fatal intracerebral (lobar) haemorrhage. CAA may also contribute to white matter lesions (myelin loss) in AD by inducing ischaemia through autoregulatory dysfunction. Although the Abeta protein deposited within blood vessels in AD is similar in chemical composition to that deposited in the brain parenchyma in SP, there is no clear relationship between the 2 pathologies. Indeed, when CAA is high, SP formation may be low, and vice versa. As if to emphasise these differences, Abeta within CAA is mostly Abeta40 whereas that within SP is Abeta42. Such compositional differences may reflect differences in source, with Abeta in SP being derived from nerve cells and Abeta in CAA having a local vascular origin. Although certain inherited forms of CAA with cerebral haemorrhage are associated with autosomal dominant mutations in APP and other genes (cystatin-C, transthyretin, gelsolin, ABrit, ADan), in most cases of AD CAA does not associate clearly with any genetic risk factor other than APO E beta4 allele, which appears to increase the severity of CAA in a dose dependent manner, especially within the occipital cortex. Genotype/phenotype correlations may be helpful in understanding the development of CAA in AD and other disorders. Why blood vessels in the occipital lobe should be most susceptible to CAA in AD remains unclear, though this pattern of blood vessel involvement does not seem to be recapitulated in other disorders in which CAA is the principal pathological change.

Alzheimer Disease↗

PubMed2003

Negative association between amyloid plaques and cerebral amyloid angiopathy in Alzheimer's disease.

Cerebral amyloid angiopathy (CAA) is an important, though still relatively neglected, aspect of the pathology of Alzheimer's disease (AD), and both the source of amyloid beta protein (Abeta) in CAA, and its relationship to senile plaque (SP) Abeta, remain unclear. We have investigated the relationship between Abeta deposition in SP and CAA in four regions of brain from 69 patients with AD in order to gain insight into the pathogenetic mechanism(s) underlying these pathologies. CAA was present to some degree in all 69 patients, with the occipital cortex being affected more often and more severely than frontal, temporal and parietal cortices. By definition, SPs were present in all brain areas in all 69 patients, with greater uniformity of distribution than CAA, though the occipital cortex was less severely affected than the other brain regions. There was no significant (positive) correlation between CAA rating and that of SP for any one cortical region, but on combining data from all four regions there was a significant inverse correlation (P=0.037) between CAA and SP ratings. Such data suggest that the cellular sources and mechanisms leading to Abeta deposition as SP or CAA are likely to differ and may proceed independently of each other.

Aged↗