Amount Of Amyloid Deposition Research Articles

Renal AA Amyloidosis in Ankylosing Spondylitis: A Case Report

Ankylosing spondylitis (AS) is a chronic inflammatory joint disease of seronegative spondyloarthropathies (SpA). Secondary amyloid A amyloidosis (Amyloidosis AA) is an uncommon complication of ankylosing spondylitis (AS). Amyloidosis AA is a systemic disease characterized by amyloid deposition in many organs including kidneys. An amyloid fibril formation starts with inappropriate folding of amyloidogenic precursor proteins. The amyloid fibrils have a typical appearance on light microscope that could be easily identified. The classification of secondary amyloidosis is based on the precursor proteins that form amyloid fibrils along with systemic and local distribution of amyloid deposition. Renal involvement is most frequent in systemic amyloidosis. The clinical manifestation of renal amyloidosis differs depending on the type of amyloid protein with the location and amount of amyloid deposition. The treatment of amyloidosis should be focused on managing symptoms and stabilizing amyloid protein.

SUVR quantification using attention-based 3D CNN with longitudinal Florbetapir PET images in Alzheimer’s disease

PurposeFlorbetapir PET images provide valuable information about the amount of amyloid deposition in the brain due to neurodegenerative diseases, which helps in the prognosis of patients. The purpose of this study is to develop a system that helps in the automatic amyloid quantification of the standard uptake value ratio so that drug treatments could be effectively determined. Methods2647 Florbetapir PET images obtained from multiple centres of Alzheimer Disease Neuroimaging Initiative (ADNI) and an external dataset of 1413 scans from the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s study are used to design and test the proposed 3D CNN attention-based model to quantify the amyloid deposits. Only 80% of scans from the ADNI dataset are used to train the model. The remaining 20% of scans from ADNI and the external dataset are used for testing the trained model. ResultsThe proposed model achieves a root mean square error of 0.0362 and a mean absolute error of 0.026 on separate hold-out test data from ADNI and a root mean square error of 0.058 and a mean absolute error of 0.044 Anti-Amyloid Treatment in Asymptomatic Alzheimer’s study dataset. A graphical user interface is developed for the proposed model which will display a slice of the Florbetapir PET volume and its predicted standard uptake value ratio. Conclusion3D CNN architecture with both spatial and channel attention provided better results when compared to models without attention. The proposed model proves to be an efficient tool in the automatic amyloid standard uptake value ratio quantification.

Cognitive Trajectories and Associated Biomarkers in Patients with Mild Cognitive Impairment.

To diagnose mild cognitive impairment (MCI) patients at risk of progression to dementia is clinically important but challenging. We classified MCI patients based on cognitive trajectories and compared biomarkers among groups. This study analyzed amnestic MCI patients with at least three Clinical Dementia Rating (CDR) scores available over a minimum of 36 months from the Alzheimer's Disease Neuroimaging Initiative database. Patients were classified based on their progression using trajectory modeling with the CDR-sum of box scores. We compared clinical and neuroimaging biomarkers across groups. Of 569 eligible MCI patients (age 72.7±7.4 years, women n = 223), three trajectory groups were identified: stable (58.2%), slow decliners (24.6%), and fast decliners (17.2%). In the fifth year after diagnosis, the CDR-sum of box scores increased by 1.2, 5.4, and 11.8 points for the stable, slow, and fast decliners, respectively. Biomarkers associated with cognitive decline were amyloid-β 42, total tau, and phosphorylated tau protein in cerebrospinal fluid, hippocampal volume, cortical metabolism, and amount of cortical and subcortical amyloid deposits. Cortical metabolism and the amount of amyloid deposits were associated with the rate of cognitive decline. Data-driven trajectory analysis provides new insights into the various cognitive trajectories of MCI. Baseline brain metabolism, and the amount of cortical and subcortical amyloid burden can provide additional information on the rate of cognitive decline.

Local administration of amyloid enhancing factor initiates in situ amyloid A deposition followed by systemic lesions in mice.

Amyloid A (AA) amyloidosis is experimentally transmissible in some animal species, such as mice and chickens. While the spleen is important as the initial deposition site in the transmission of AA amyloidosis, it is not essential for establishing the transmission, and its role is not precisely understood. In this study, to clarify why the spleen is the first site of deposition in transmissible AA amyloidosis, we administered amyloid enhancing factor, which is AA fibrils extracted from AA amyloidosis affected mouse to local organs (liver, spleen, kidney, stomach wall, and Peyer's patches), to tail vein and into peritoneum; then compared the amyloid distribution. Interestingly, initial amyloid deposition was observed at the administration site in each administered organ, not just the spleen. Furthermore, the amount of amyloid deposition in intra-organ administration groups was larger than that of the intravenous or intraperitoneal administration groups. This study indicates that locally exposed AEF initiates in situ amyloid deposition, from which amyloid deposition spreads throughout the body.

99mTc-DPD myocardial uptake and regional longitudinal strain in aTTR amyloidosis cardiomyopathy

Abstract Funding Acknowledgements Type of funding sources: None. BACKGROUND amyloid cardiomyopathy is characterized by a typical "apical sparing" pattern of systolic longitudinal strain (LS) as visualized by echocardiography. Strain is well preserved at the apex of the left ventricle (LV) with a gradient from apex to base and the greatest impairment in the basal segments. The reason of this distribution is not clear. It could be a function of different amount of amyloid deposition. SPECT images using Technetium 99m bone tracers have shown a distribution mimicking regional LS. PURPOSE to compare regional myocardial LS and myocardial distribution of 99m Technetium-DPD (99m Tc-DPD) uptake in patients affected by aTTR amyloidosis cardiomyopathy. METHODS between 2016-2021 70 patients referred to our Cardiology Unit with heart failure/shortness of breath on exertion and showing significant left ventricular hypertrophy at 2-D echocardiography underwent 99m Tc-DPD scintigraphy to test the presence of cardiac amyloid. Grade 2-3 myocardial uptake at 180 minutes in the absence of abnormalities in the analysis of serum free light chains and serum and urine protein electrophoresis with immunofixation was considered sufficient for the diagnosis of aTTR amyloidosis. When scintigraphy was positive a SPECT study was performed to obtain semi quantitative measurements of segmental myocardial uptake (expressed as % of total myocardial uptake). Regional mean count was calculated by using a 6 basal, 12 mid and 2 apical segmental model. All patients underwent standard and 2D speckle tracking echocardiography. Mean systolic LS was calculated for each of 18 segments and mean basal (6 segments), mean mid (6 segments) and mean apical (6 segments) LS was calculated. RESULTS 46/70 patients had a positive scan and fulfilled criteria for aTTR amyloidosis. 33/46 had SPECT analysis. Male/female ratio was 29/4, age = 80 ± 6 years; 9/33 aortic stenosis; 19/33 carpal tunnel; 25/33 wild-type aTTR (4/33 ongoing genetic test); LV mass-=228 ± 48 g/m2; RWT = 0,73 ± 0,14; EF= 53 ± 9; EF to GLS ratio= 5,6 ±1,8. ANOVA showed a significant difference between basal, mid and apical strain as well as between basal, mid and apical uptake (-5,5 ± 4,4; -9,6 ± 3,2; -15,9 ± 5,6; p < 0,001; 55 ± 14; 62 ± 10; 51 ± 11; p = 0,0019). Comparison between groups showed that mean LS at the apex was significantly lower compared to basal and mid mean LS (Bonferroni test, p < 0,001) (Fig 1). Apical myocardial uptake was significantly lower compared to mid segment but not to basal (Bonferroni test, p = 0,02, p = 0,6 respectively) (Fig 1). Spearman’s test showed a correlation between LS and myocardial 99m Tc-DPD uptake (p = 0,01, Rho = 0,24). CONCLUSIONS Our data show that in this group of patients with cardiac aTTR amyloidosis apical LS is significantly lower compared to basal and mid segments and apical myocardial 99m Tc-DPD uptake is significantly lower compared to mid segments; a correlation between myocardial 99m Tc-DPD uptake distribution and the degree of LS impairment is present. Abstract Figure.

Dietary Intake of Rosmarinic Acid Increases Serum Inhibitory Activity in Amyloid A Aggregation and Suppresses Deposition in the Organs of Mice.

Serum amyloid A (SAA) is one of the most important precursor amyloid proteins and plays a vital step in AA amyloidosis, although the underlying aggregation mechanism has not been elucidated. Since SAA aggregation is a key step in this pathogenesis, inhibitors are useful to prevent and treat AA amyloidosis, serving as tools to investigate the pathogenic mechanism. In this study, we showed that rosmarinic acid (RA), which is a well-known inhibitor of the aggregation of amyloid β (Aβ), displayed inhibitory activity against SAA aggregation in vitro using a microliter-scale high-throughput screening (MSHTS) system with quantum-dot nanoprobes. Therefore, we evaluated the amyloid aggregation inhibitory activity of blood and the deposition of SAA in organs by feeding mice with Melissa officinalis extract (ME) containing RA as an active substance. Interestingly, the inhibitory activity of ME-fed mice sera for SAA and Aβ aggregation, measured with the MSHTS system, was higher than that of the control group. The amount of amyloid deposition in the organs of ME-fed mice was lower than that in the control group, suggesting that the SAA aggregation inhibitory activity of serum is associated with SAA deposition. These results suggest that dietary intake of RA-containing ME enhanced amyloid aggregation inhibitory activity of blood and suppressed SAA deposition in organs. This study also demonstrated that the MSHTS system could be applied to in vitro screening and to monitor comprehensive activity of metabolized foods adsorbed by blood.

Schwann cell and endothelial cell damage in transthyretin familial amyloid polyneuropathy.

To examine the morphology of Schwann cells and endoneurial microvessels with electron microscopy. Sural nerve biopsy specimens from 49 patients with familial amyloid polyneuropathy (FAP) with transthyretin Val30Met mutation were assessed. Patients included 11 early-onset cases from endemic foci and 38 late-onset cases from nonendemic areas. Loss of nerve fibers with or without neighboring amyloid deposition was a common feature. The amount of amyloid deposition was greater relative to the extent of nerve fiber loss in early-onset cases than in late-onset cases. The atrophy of Schwann cells, particularly nonmyelinating Schwann cells, that were apposed to amyloid fibrils was more conspicuous in early-onset cases than in late-onset cases. The numbers of endothelial cell nuclei, endothelial cell profiles, and occluded microvessels were significantly increased in the patients with FAP compared with 37 patients with nutritional/alcoholic neuropathies (p < 0.05, 0.01, and 0.01, respectively). Findings suggestive of the disruption of blood-nerve barriers such as the loss of tight junctions and the fenestration of endothelial cells were also found more frequently in the patients with FAP (p < 0.001), regardless of the presence or absence of amyloid deposition. These findings suggest that direct insult of amyloid fibrils causes Schwann cell damage, resulting in the predominant loss of small-fiber axons characteristic of early-onset cases. In addition, vasculopathy may participate in the pathogenesis of neuropathy, particularly in late-onset cases.

Experimental transmission of systemic AA amyloidosis in autoimmune disease and type 2 diabetes mellitus model mice

AA amyloidosis is a protein misfolding disease characterized by extracellular deposition of amyloid A (AA) fibrils. AA amyloidosis has been identified in food animals, and it has been postulated that AA amyloidosis may be transmissible to different animal species. Since the precursor protein of AA fibrils is serum amyloid A (SAA), which is an inflammatory acute phase protein, AA amyloidosis is considered to be associated with inflammatory diseases such as rheumatoid arthritis. Chronic diseases such as autoimmune disease and type 2 diabetes mellitus could be potential factors for AA amyloidosis. In this study, to examine the relationship between the induction of AA amyloidosis and chromic abnormalities such as autoimmune disease or type 2 diabetes mellitus, amyloid fibrils from mice, cattle, or chickens were experimentally injected into disease model mice. Wild-type mice were used as controls. The concentrations of SAA, IL-6, and IL-10 in autoimmune disease model mice were higher than those of control mice. However, induction of AA amyloidosis in autoimmune disease and type 2 diabetes mellitus model mice was lower than that in control mice, and the amount of amyloid deposits in the spleens of both mouse models was lower than that of control mice according to Congo red staining and immunohistochemistry. These results suggest that factors other than SAA levels, such as an inflammatory or anti-inflammatory environment in the immune response, may be involved in amyloid deposition.

Age and amyloid effects on human central nervous system amyloid-beta kinetics.

Age is the single greatest risk factor for Alzheimer's disease (AD), with the incidence doubling every 5 years after age 65. However, our understanding of the mechanistic relationship between increasing age and the risk for AD is currently limited. We therefore sought to determine the relationship between age, amyloidosis, and amyloid-beta (Aβ) kinetics in the central nervous system (CNS) of humans. Aβ kinetics were analyzed in 112 participants and compared to the ages of participants and the amount of amyloid deposition. We found a highly significant correlation between increasing age and slowed Aβ turnover rates (2.5-fold longer half-life over five decades of age). In addition, we found independent effects on Aβ42 kinetics specifically in participants with amyloid deposition. Amyloidosis was associated with a higher (>50%) irreversible loss of soluble Aβ42 and a 10-fold higher Aβ42 reversible exchange rate. These findings reveal a mechanistic link between human aging and the risk of amyloidosis, which may be owing to a dramatic slowing of Aβ turnover, increasing the likelihood of protein misfolding that leads to deposition. Alterations in Aβ kinetics associated with aging and amyloidosis suggest opportunities for diagnostic and therapeutic strategies. More generally, this study provides an example of how changes in protein turnover kinetics can be used to detect physiological and pathophysiological changes and may be applicable to other proteinopathies.

The effects of white matter hyperintensities and amyloid deposition on Alzheimer dementia.

Background and purposeElevated levels of amyloid deposition as well as white matter damage are thought to be risk factors for Alzheimer Disease (AD). Here we examined whether qualitative ratings of white matter damage predicted cognitive impairment beyond measures of amyloid.Materials and methodsThe study examined 397 cognitively normal, 51 very mildly demented, and 11 mildly demented individuals aged 42–90 (mean 68.5). Participants obtained a T2-weighted scan as well as a positron emission tomography scan using 11[C] Pittsburgh Compound B. Periventricular white matter hyperintensities (PVWMHs) and deep white matter hyperintensities (DWMHs) were measured on each T2 scan using the Fazekas rating scale. The effects of amyloid deposition and white matter damage were assessed using logistic regressions.ResultsLevels of amyloid deposition (ps < 0.01), as well as ratings of PVWMH (p < 0.01) and DWMH (p < 0.05) discriminated between cognitively normal and demented individuals.ConclusionsThe amount of amyloid deposition and white matter damage independently predicts cognitive impairment. This suggests a diagnostic utility of qualitative white matter scales in addition to measuring amyloid levels.

Steady turnover of amyloid fibril proteins in gastric mucosa after liver transplantation in familial amyloid polyneuropathy

Introduction: Our previous study demonstrated marked regression of amyloid deposits in abdominal fat tissues of familial amyloid polyneuropathy (FAP) patients treated with liver transplantation (LT). To determine whether similar changes in deposited amyloid can also occur in other organs, we examined gastric mucosal amyloid before and after LT in FAP patients with ATTRV30M.Methods: We histopathologically and biochemically investigated gastric mucosal amyloid before and after LT in six FAP patients with ATTRV30M.The amounts of amyloid deposits in biopsied gastric mucosa were determined by microscopy, and the proportion of wild-type transthyretin (TTR) in extracted amyloid fibril proteins was assayed by liquid chromatography-ion trap mass spectrometry. Similar examinations were also performed in 21 untreated FAP patients and 13 transplanted patients with ATTRV30M.Results: The amount of deposited amyloid was not markedly different before and after LT in six patients. However, the composition ratios of wild-type TTR in gastric mucosal amyloid increased markedly from 20.0% ± 11.4% before LT to 43.2% ± 13.8% after LT. In addition, the ratio of wild-type TTR in all transplanted patients was significantly higher than that in untransplanted patients (72.7% ± 25.5%, 23.8% ± 14.3%, respectively).Conclusions: Our results showed that the components of amyloid fibril proteins in gastric mucosa of transplanted FAP patients are different from those in untreated patients: a significant portion of preexisting ATTRV30M-derived amyloid seemed to be replaced by wild-type TTR-derived amyloid postoperatively, indicating that continuous turnover of amyloid deposits can occur in all organs in transplanted FAP patients. It was also confirmed that wild-type TTR plays an important role in the pathogenesis of postoperative amyloid deposition in transplanted FAP patients.

Treatment with D3 Removes Amyloid Deposits, Reduces Inflammation, and Improves Cognition in Aged AβPP/PS1 Double Transgenic Mice

One of the characteristic pathological hallmarks of Alzheimer's disease (AD) is neuritic plaques. The sequence of events leading to deposition of amyloid-β (Aβ) peptides in plaques is not clear. Here we investigate the effects of D3, an Aβ oligomer directed D-enantiomeric peptide that was obtained from a mirror image phage display selection against monomeric or small oligomeric forms of Aβ42, on Aβ deposition in aged AβPP/PS1 double transgenic AD-model mice. Using Alzet minipumps, we infused the brains of these AD model mice for 8 weeks with FITC-labeled D3, and examined the subsequent changes in pathology and cognitive deficits. Initial cognitive deficits are similar comparing control and D3-FITC-treated mice, but the treated mice show a significant improvement on the last day of testing. Further, we show that there is a substantial reduction in the amount of amyloid deposits in the animals treated with D3-FITC, compared to the control mice. Finally, the amount of activated microglia and astrocytes surrounding Aβ deposits is dramatically reduced in the D3-FITC-treated mice. Our findings demonstrate that treatments with the high affinity Aβ42 oligomer binding D-enantiomeric peptide D3 significantly decrease Aβ deposits and the associated inflammatory response, and improve cognition even when applied only at late stages and high age. Together, this suggests that the treatment reduces the level of Aβ peptide in the brains of AβPP/PS1 mice, possibly by increasing Aβ outflow from the brain. In conclusion, treatments with this D-peptide have great potential to be successful in AD patients.

Estimation of cardiac amyloid infiltration with myocardial T1 mapping correlates with severity of cardiac involvement

Background Post-contrast myocardial T1-mapping with cardiac magnetic resonance (CMR) has shown usefulness in the diagnosis of cardiac amyloid. A lower value indicates increase in extracellular volume and thereby amyloid deposition. The aim of this study is to assess the association between the amount of amyloid deposition as estimated by the degree of post-contrast myocardial T1 reduction and the severity of left ventricular (LV) involvement in cardiac amyloidosis. Methods Consecutive patients referred for 3.0 Tesla CMR with a final diagnosis of cardiac amyloidosis (defined as positive cardiac biopsy and/or typical diffuse, predominantly subendocardial pattern of delayed contrast enhancement) were retrospectively evaluated. The septal E/E’ ratio as an index of LV filling pressures was measured with doppler echocardiography (n=18, 69%). Indexed LV volumes and mass, LV ejection fraction, and LV basal anteroseptal and inferolateral wall thicknesses were determined from cine CMR. Hemodynamic data from cardiac catheterization and brain natriuretic peptide (BNP) serum levels were available in 9 (36%) and 14 (54%) patients. respectively. Myocardial, endocardial, blood, and skeletal muscle were quantified after Gd-DTPA administration on a previously validated Look-Locker sequence using dedicated software. Correlations between myocardial T1 values and other indices of cardiac involvement were performed using Pearson correlation coefficients. Results We included 26 patients (17 males [65.4%], age 68±13 years) with a final diagnosis of cardiac amyloid. There was an inverse correlation between myocardial/blood T1 ratio and basal anteroseptal (r=-0.519, p=0.008) and inferolateral (r=-0.498, p=0.011) wall thickness. Similarly endocardial/blood T1 ratio was inversely correlated with basal anteroseptal (r=-0.595, p=0.002; Figure) and inferolateral (r=-0.429, p=0.032) wall thickness. No significant associations were noted with LV volumes, ejection fraction, or mass. Otherwise, myocardial and endocardial T1 time showed an inverse correlation with BNP (r=-0.659, p=0.014 and r=-0.610, p=0.027 respectiveley). In addition, myocardial/skeletal muscle T1 ratio showed

Impact of aging on the progression of neuropathy after liver transplantation in transthyretin Val30Met amyloidosis

Information related to the long-term follow-up of neuropathy in patients with familial amyloid polyneuropathy after liver transplantation is still scarce. We describe the neuropathic features of 3 patients with the transthyretin Val30Met mutation. Each patient underwent liver transplantation at an early stage of neuropathy, as indicated by the absence of motor dysfunction and relative preservation of myelinated fibers in sural nerve biopsy specimens. Although the patient with late-onset disease (at age 60 years) presented with the least amount of amyloid deposition, he had neuropathic progression after liver transplantation. An older early-onset (at age 40 years) patient reported a slight exacerbation of both somatic and autonomic neuropathic symptoms 10 years after transplantation. However, the younger early-onset (at age 28 years) patient did not exhibit characteristics suggestive of neuropathy 7 years after transplantation. Aging may determine the progression of neuropathy after liver transplantation.

Significant association between renal function and amyloid-positive area in renal biopsy specimens in AL amyloidosis

BackgroundThe kidney is a major target organ for systemic amyloidosis that often affects the kidney including proteinura, and elevated serum creatinine (Cr). The correlation between amount of amyloid deposits and clinical parameters is not known. The aim of this study was to clarify correlation the amyloid area in all renal biopsy specimen and clinical parameters.MethodsFifty-eight patients with an established diagnosis of AL amyloidosis participated in the study. All patients showed amyloid deposits in renal biopsies. We retrospectively investigated the correlation between clinical data and amyloid occupied area in whole renal biopsy specimens.ResultsThe area occupied by amyloid was less than 10% in 57 of the 58 patients, and was under 2% in 40. For statistical analyses, %amyloid-positive areas were transformed to common logarithmic values (Log10%amyloid). Cr showed significant correlation with Log10%amyloid and estimated glomerular filtration rate (eGFR) showed the significant negative correlation. Patient age, cleatinine clearance (Ccr), blood urea nitorogen, and urinary protein was not significantly correlated with Log10%amyloid. The correlation with other clinical factors such as sex, and serum concentrations of total protein, albumin, immunoglobulins, compliments was evaluated. None of these factors significantly correlated with Log10%amyloid. According to sex- and age- adjusted multiple linear regression analysis, Log10%amyloid had significant positive association with Cr and significant negative association with eGFR.ConclusionThere is significant association between amyloid-positive area in renal tissue and renal function, especially Cr and eGFR. The level of Cr and eGFR may be a marker of amount of amyloid in renal tissue.

Atypical AA amyloid deposits in bovine AA amyloidosis

In bovine amyloid protein A (AA) amyloidosis, amyloid deposits are typically observed in the kidney and spleen at necropsy. To determine the distribution of amyloid deposits in cows affected with AA amyloidosis, we examined organs known to be sites of amyloid deposits that are also processed for human consumption in 14 cows: 11 with typical clinical symptoms (typical amyloidosis) and three with no typical clinical symptoms (atypical amyloidosis). We found unusually high amounts of amyloid deposits in the tongue and other organs in all 14 cows regardless of the presence or absence of clinical amyloidosis symptoms. Cows with typical amyloidosis had heavier amyloid deposits in the spleen and renal glomeruli than cows with atypical amyloidosis. From clinical symptoms and histological examinations, we found that cows with typical and atypical amyloidosis can be classified into two groups, class I and class II, according to the presence or absence of heavy amyloid deposits in the spleen and renal glomeruli. However, no significant differences were observed between the amyloid fibrils of class I and class II amyloidosis by electron microscopy and Western blot analysis.

Significant association between renal function and area of amyloid deposition in kidney biopsy specimens in reactive amyloidosis associated with rheumatoid arthritis

The kidney is a major target organ for systemic amyloidosis, resulting in proteinuria and an elevated serum creatinine level. In patients with reactive amyloidosis associated with rheumatoid arthritis, a correlation between the amount of amyloid deposits and clinical parameters is not known. The purpose of this study was to clarify the association between various factors including renal function and the area of amyloid deposition in these patients. Fifty-eight patients with an established diagnosis of reactive AA amyloidosis were studied. We retrospectively investigated the correlation between clinical data and the area occupied by amyloid in renal biopsy specimens. All the patients showed amyloid deposits in renal tissues, and the percentage of the area occupied by amyloid was <10% in 54 of them. Mesangial proliferative glomerulonephritis and membranous nephropathy were frequently combined with renal amyloidosis. For statistical analyses, the percentage of the area occupied by amyloid was transformed to a common logarithmic value (Log(10) % amyloid), as the histograms showed a log-normal distribution. Log(10) % amyloid was found to be correlated with age, creatinine (Cr) level, creatinine clearance (Ccr), blood urea nitrogen (BUN) level, and the estimated glomerular filtration rate (eGFR). Multiple linear regression analyses were then performed to examine the sex- and age-adjusted association between Log(10) % amyloid and each of the clinical variables. Cr, Ccr, BUN, UA, CRP, and eGFR were significantly correlated with Log(10) % amyloid, but urinary protein was not. There was a significant correlation between the area of amyloid deposition in renal tissue and parameters of renal function, especially Cr and Ccr. If amyloid deposition in renal tissue can be arrested or prevented, then it may be possible to maintain renal function at an acceptable level.

Sporadic cerebral amyloid angiopathy—an important cause of cerebral haemorrhage in older people

Cerebral amyloid angiopathy (CAA) is an important cause of primary intracerebral haemorrhage (PICH) in older people, accounting for approximately 10% of all types of PICH. The amount of amyloid deposition in the vessels and vasculopathic changes determine the propensity to PICH. The risk factors of CAA include advanced age and the presence of certain alleles of apolipoprotein E. There are no specific clinical features of CAA-related PICH, although lobar, recurrent or multiple simultaneous haemorrhages in older patients should raise suspicion of its diagnosis. A definitive diagnosis of CAA requires pathological examination of the affected tissue. However, with modern imaging techniques, it is possible to make a diagnosis of 'probable CAA' in patients presenting with PICH. Gradient-echo magnetic resonance imaging is a sensitive, non-invasive technique for identifying small haemorrhages in life. Currently, there is no specific treatment available for CAA. Recent advances in the immunopathology and pathogenesis of CAA are expected to help in developing specific anti-amyloid therapy.

Protofibril Formation of Amyloid β-Protein at Low pH via a Non-cooperative Elongation Mechanism

Deposition of the amyloid beta-protein (Abeta) in senile or diffuse plaques is a distinctive feature of Alzheimer's disease. The role of Abeta aggregates in the etiology of the disease is still controversial. The formation of linear aggregates, known as amyloid fibrils, has been proposed as the onset and the cause of pathological deposition. Yet, recent findings suggest that a more crucial role is played by prefibrillar oligomeric assemblies of Abeta that are highly toxic in the extracellular environment. In the present work, the mechanism of protofibril formation is studied at pH 3.1, starting from a solution of oligomeric precursors. By combining static light scattering and photon correlation spectroscopy, the growth of the mass and the size of aggregates are determined at different temperatures. Analysis and scaling of kinetic data reveal that under the studied conditions protofibrils are formed via a single non-cooperative elongation mechanism, not prompted by nucleation. This process is well described as a linear colloidal aggregation due to diffusion and coalescence of growing aggregates. The rate of elongation follows an Arrhenius law with an activation enthalpy of 15 kcal mol(-1). Such a value points to a conformational change of peptides or oligomers being involved in binding to protofibrils or in general to a local reorganization of each aggregate. These results contribute to establishing a clearer relation at the molecular level between the fibrillation mechanism and fibrillar precursors. The observation of a non-cooperative aggregation pathway supports the hypothesis that amyloid formation may represent an escape route from a dangerous condition, induced by the presence of toxic oligomeric species.

This month in J Lab Clin Med: Issue highlights for August 2001

This month in J Lab Clin Med: Issue highlights for August 2001