Extent Of Amyloid Deposition Research Articles

Surface Structure of Amyloid-β Fibrils Contributes to Cytotoxicity

Amyloid beta (Abeta) toxicity has been hypothesized to initiate the pathogenesis of Alzheimer's disease (AD). The characteristic fibrillar morphology of Abeta-aggregates, that constitute the main components of senile plaque, has long been considered to account for the neurotoxicity. But recent reports argue against a primary role for mature fibrils in AD pathogenesis because of the lack of a robust correlation between the severity of neurological impairment and the extent of amyloid deposition. Toxicity from the soluble prefibrillar intermediate entity of aggregates often called oligomer has recently proposed a plausible explanation for this inconsistency. An alternative explanation is based on the observation that certain amyloid fibril morphologies are more toxic than others, indicating that not all amyloid fibrils are equally toxic. Here, we report that it is not only the beta-sheeted fibrillar structure but also the surface physicochemical composition that affects the toxicity of Abeta fibrils. For the first time, colloidal gold was used to visualize by electron microscopy positive-charge clusters on Abeta fibrils. Chemical modifications as well as point-mutated Abeta synthesis techniques were applied to change the surface structures of Abeta and to show how local structure affects surface properties that are responsible for electrostatic and hydrophobic interactions with cells. We also report that covering the surface of Abeta fibers with myelin basic protein, which has surface properties contrary to those of Abeta, suppresses Abeta toxicity. On the basis of these results, we propose that the surface structure of Abeta fibrils plays an important role in Abeta toxicity.

Islet amyloid: a critical entity in the pathogenesis of type 2 diabetes.

Islet amyloid deposition is a pathogenic feature of type 2 diabetes, and these deposits contain the unique amyloidogenic peptide islet amyloid polypeptide. Autopsy studies in humans have demonstrated that islet amyloid is associated with loss of beta-cell mass, but a direct role for amyloid in the pathogenesis of type 2 diabetes cannot be inferred from such studies. Animal studies in both spontaneous and transgenic models of islet amyloid formation have shown that amyloid forms in islets before fasting hyperglycemia and therefore does not arise merely as a result of the diabetic state. Furthermore, the extent of amyloid deposition is associated with both loss of beta-cell mass and impairment in insulin secretion and glucose metabolism, suggesting a causative role for islet amyloid in the islet lesion of type 2 diabetes. These animal studies have also shown that beta-cell dysfunction seems to be an important prerequisite for islet amyloid formation, with increased secretory demand from obesity and/or insulin resistance acting to further increase islet amyloid deposition. Recent in vitro studies suggest that the cytotoxic species responsible for islet amyloid-induced beta-cell death are formed during the very early stages of islet amyloid formation, when islet amyloid polypeptide aggregation commences. Interventions to prevent islet amyloid formation are emerging, with peptide and small molecule inhibitors being developed. These agents could thus lead to a preservation of beta-cell mass and amelioration of the islet lesion in type 2 diabetes.

Glomerular crescents in renal amyloidosis: an epiphenomenon or distinct pathology?

There have been several reports of cases of renal amyloidosis with glomerular crescents. However, it is not clear whether the association is fortuitous or pathogenic related. The present study analyzed 105 cases of renal amyloidosis (61 autopsy cases and 44 biopsy cases) and found glomerular crescents in 14 (13.3%) cases. Among the 14 cases with crescents, a female predominance was noted (male: female, 3: 11) and rheumatoid arthritis was the most common primary disease of amyloidosis. Immunohistochemical analysis demonstrated amyloid protein of AA type in 12 cases. According to the histologic classification, there were 11 cases of mesangial nodular type, which was almost exclusively accompanied by AA amyloid deposition. Of note, the incidence of crescents neither correlated with the extent of amyloid deposition nor the presence of nephrotic syndrome. By contrast, localization of amyloid deposition was closely related to crescent formation. Moreover, electron microscopic observation displayed rupture of the glomerular basement membrane at the site of amyloid deposition. Our results indicated that glomerular crescents were more frequently associated with renal amyloidosis than previously appreciated. Rupture of the fragile glomerular basement membrane by amyloid deposition, as revealed by immunostaining and electron microscopy, may be the mechanism of crescent formation. We suggest that glomerular crescents are a distinct pathology associated with renal amyloidosis, not fortuitous conditions.

Orthotopic liver transplantation for familial amyloidotic polyneuropathy: A pathological study

Familial amyloidotic polyneuropathy (FAP), a hereditary form of systemic amyloidosis with clinically significant neuropathy and cardiomyopathy, is caused by a genetic defect of the transthyretin gene, which is mostly synthesized in the liver. Orthotopic liver transplantation (OLT) is thought to eliminate the amyloidogenic protein and currently is the only definitive treatment for this disorder. The aim of this study was to define the distribution and extent of amyloid deposition in tissues from these patients and evaluate the suitability of the resected FAP livers for transplantation into non-FAP patients. Surgical specimens from 14 patients removed at the time of OLT and autopsy tissues from 3 of the 14 were examined histologically using hematoxylin and eosin and Congo red-stained sections. The extent of amyloid deposits was evaluated, semiquantitatively graded from negative to marked, and correlated with clinical course and patient outcome. Amyloid deposits were consistently seen in hilar and vagus nerves. Liver lobular involvement was minimal in 1 and absent in the other 13 cases, with portal arterial amyloid deposits seen in 7 cases. At autopsy, extensive amyloid deposition in the heart was seen in all 3 cases with involvement of the conduction system. The extent of amyloid deposition at OLT did not correlate with the duration of symptoms before OLT or patient outcome after OLT. In conclusion, liver parenchymal involvement in FAP is minimal, and these explants are suitable for grafting in non-FAP patients. The recipients of such grafts must be carefully observed for the development of any amyloid-related disease, particularly cardiomyopathy. Of the tissues removed at OLT, the histopathologic confirmation of FAP is most consistently made by the examination of hilar and vagus nerves.

Neurofibrillary pathology — correlation with hippocampal formation atrophy in Alzheimer disease

The three-dimensionally reconstructed hippocampal formations in three patients with very severe, immobile Alzheimer disease (AD) and three age-matched nondemented individuals were examined for a correlation between atrophy of hippocampal formation subdivisions and neurofibrillary changes, neuronal loss, and extent of amyloid deposition in plaques and vessels. In AD, a similar severe volume loss was observed in both cellular layers and layers composed of fibers. A strong correlation between the decrease in the volume of hippocampal formation subdivisions and the decrease in the total number of neurons suggests a causative role for neuronal loss in hippocampal formation volumetric loss. Strong regional correlations between the relative decreases in the total number of neurons and the relative increases in the total number of neurofibrillary tangles implicates neurofibrillary pathology as a possible etiologic proximate factor in neuronal and volumetric loss in the hippocampal formation of AD patients.

The extent of amyloid deposition in brain in patients with Down's syndrome does not depend upon the apolipoprotein E genotype

The extent of deposition of amyloid β protein (Aβ) was investigated in 20 elderly patients with Down's syndrome, using the endspecific monoclonal antibodies BC05 and BA27 to detect the presence of A β 42(43) and A β 40 (respectively), and related to apolipoprotein E (ApoE) genotype. No significant differences in the amount of Aβ deposited in the brain, either as A β 42(43) or A β 40 were noted in patients possessing an ApoE E4 allele, compared to those without. Patients with an ApoE E4 allele in general died at an earlier age than those with only ApoE E3 alleles, the latter in turn being outlived by those with an ApoE E2 allele. In Down's syndrome therefore, ApoE may influence the timing of onset, or the rate of progression, of disease but without affecting the type or total amount of pathology accumulated.

Amyloidosis and endomyocardial biopsy: Correlation of extent and pattern of deposition with amyloid immunophenotype in 100 cases

The heart is subject to involvement by primary (AL), senile (AS), and familial (AF) forms of amyloidosis, but the frequency, severity, and therapy of amyloid-related cardiac symptoms differ depending on the type of amyloidosis present. Endomycardial biopsy is a safe and reliable procedure for diagnosing cardiac amyloidosis, and immunohistochemical staining of routinely processed biopsy specimens can be performed to classify the type of amyloid present. However, whether or not the type can be determined from the histologic extent and pattern of amyloid deposition is unclear. Endomyocardial biopsy specimens from 100 patients with cardiac amyloidosis (74 AL, 22 AS, 4 AF) were examined, and the histologic extent and pattern of amyloid deposition were correlated with the amyloid immunophenotype. No difference in the extent of amyloid deposition was identified among the three types. Interstitial nodules of amyloid were more common in AS (82%) than in AL (50%, p = 0.0129), whereas vascular involvement was more frequently observed in AL (88%) than in AS (26%, p < 0.0001). Endocardial and interstitial pericellular deposition occurred with similar frequencies in both groups. Although statistically significant differences existed in the patterns of amyloid deposition, they did not allow reliable distinction between the different types in individual cases. Consequently, in older patients without serum or urinary light chains, immunohistochemical staining is recommended to distinguish AL from AS types of amyloid in cardiac biopsy tissues.

Diagnosis and monitoring of amyloidosis

The diagnosis of systemic amyloidosis is only occasionally suspected on clinical grounds alone and is more often considered when an associated condition, such as a chronic inflammatory disease or monoclonal gammopathy, is present. No blood test is diagnostic of amyloid although routine haematological and biochemical investigations have important roles in defining the underlying disease process in amyloidosis, and evaluating organ function. A number of non-invasive investigations including echocardiography, electrocardiography and soft tissue scintigraphy with bone-seeking tracers give characteristic results in some patients with amyloidosis, but are non-specific. The diagnosis can only be confirmed by demonstrating the presence of amyloid deposits in the tissues. Histology is the traditional method in routine clinical practice and is sensitive for revealing microscopic deposits and permits immunotyping of fibril proteins. Disadvantages are that biopsies are invasive, open to sampling error and can only give limited information on the distribution and extent of amyloid deposits in an individual. Scintigraphic and turnover studies with radioiodinated SAP are new specific methods for confirming the presence of amyloid in tissues, based on the affinity of SAP for all types of amyloid fibril. Labelled SAP scans survey the whole body macroscopically for the presence and anatomical distribution of amyloid in a quantitative manner, and SAP turnover studies provide information on the whole body amyloid load. Although the availability of SAP scintigraphy presently remains restricted, the technique has been used in over 400 patients with amyloid in prospective studies, and has already provided a number of new insights into the natural history of amyloidosis. These include the observation that there is a consistently poor correlation between the quantity of amyloid in an organ and the resulting degree of functional impairment. Amyloid deposits accumulate at rates which vary substantially between different organs in a single subject and between individuals with similar types of amyloidosis, even when the rates of amyloid fibril precursor protein supply are apparently similar. In some patients amyloid accumulation may plateau without any measurable alteration in the precursor supply. In patients with amyloidosis in whom the supply of fibril precursors is reduced, either as a result of therapy directed towards the underlying process or through a natural remission, substantial regression of amyloid frequently occurs. This has been observed in patients with AA, AL and variant TTR-associated amyloidosis, and is usually associated with clinical benefits. In some such cases, however, the function of affected organs may continue to deteriorate despite halting the accumulation of amyloid, presumably because irreversible structural damage has already occurred.(ABSTRACT TRUNCATED AT 400 WORDS)

Amyloid deposition in the digestive tract in casein-induced experimental amyloidosis in mice.

In mice with casein-induced experimental amyloidosis, the incidence of amyloidosis in various organs was examined in relation to time, and the extent of amyloid deposition in the digestive tract was investigated. Amyloid was deposited first in the spleen, a little later in the digestive tract, and then in the liver and kidney. In the digestive tract, amyloid appeared simultaneously in the small and large intestine, and later in the glandular stomach. Amyloid deposition was most severe in the ileum, while it was not induced in the esophagus or non-glandular stomach. Initially, amyloid deposition was observed along the small blood vessels and/or epithelial basement membranes in the lamina propria mucosa (LPM); it then extended to the stroma in the LPM. Amyloid deposition in each portion of the digestive tract had characteristic patterns in the LPM. Deposition of amyloid fibrils was confirmed by electron microscopy. The results suggest that the gastrointestinal biopsy used widely to diagnose human reactive amyloidosis is a sensitive early indicator of amyloidosis.

Regional distribution of neurofibrillary tangles and senile plaques in the cerebral cortex of elderly patients: a quantitative evaluation of a one-year autopsy population from a geriatric hospital.

Detailed analyses of the neuropathologic changes in the cerebral cortex of elderly individuals and Alzheimer's disease patients have demonstrated that certain components of the neocortical and hippocampal circuits are likely to be selectively vulnerable. Based on the distribution of neurofibrillary tangles (NFTs) and senile plaques, it has been proposed that a global corticocortical disconnection leads to the loss of integrated functions observed in Alzheimer's disease. In order to investigate the distribution of lesions associated with aging as well as with the earliest symptoms of senile dementia, we performed a quantitative neuropathologic evaluation of a large series of elderly patients representing the entire autopsy population for the year 1989 from a geriatric hospital. Among the 145 cases quantitatively assessed, there were 102 nondemented patients, 33 patients presenting clinically with globally intact intellectual function but early signs of impairment of specific cognitive functions, and 10 cases with senile dementia of the Alzheimer type. All of the cases had NFTs in layer II of the entorhinal cortex, regardless of their clinical diagnosis, and most cases had some NFTs in the CA1 field of the hippocampus. Severe pathologic changes within the inferior temporal neocortex were observed only in the demented cases. The extent of amyloid deposition was not correlated with the clinical diagnosis and seemed to be present in the neocortical areas earlier than in the hippocampal formation. Also, several cases contained NFTs without amyloid deposition, but amyloid never occurred without NFTs. These results suggest that involvement of certain structures within the hippocampal formation is a consistent feature of aging. Thus, involvement of the hippocampal formation may be a necessary, but not sufficient, condition for the clinical expression of dementia, which is likely to be more closely related to the progressive degeneration of select neuronal populations in the neocortex.

Primary amyloidosis—involving principally intrarenal blood vessels

We analysed renal biopsies from 34 nephrotic patients with renal amyloidosis, seven with primary form kappa chain (AL amyloidosis) and 27 with secondary amyloidosis associated with the other chronic diseases. Renal biopsy specimens were analysed using optical and immunofluorescence microscopy. The extent of amyloid deposits was graded from 0 to + + + +. Intrarenal blood vessel deposits were more prominent than intraglomerular in five of seven patients with AL amyloidosis, while they were identical in one, and in one, intraglomerular amyloid deposits were dominant. The results were different in the group of patients with secondary amyloidosis: a lower degree of intrarenal blood vessels deposition than glomerular was noted in 22 of 27 cases, the degree of deposition was identical in 4 of 27 cases and more expressed blood vessel deposition was present in only one case. Granular or combined deposits (granular+linear) were found on immunofluorescence microscopy in primary form, but the dominant form of deposition was amorphous in secondary amyloid.

&lt;i&gt;Schistosoma haematobium&lt;/i&gt;&lt;i&gt;-&lt;/i&gt;lnducedGlomerular Disease: An Experimental Study in the Golden Hamster

Information regarding glomerular lesions related to Schistosoma haematobium infection in man or animal are extremely lacking and disputed. The objective of this experimental study was to investigate glomerular lesions in S. haematobium-infected golden hamsters. In this work, 53 hamsters were infected with S. haematobium cercariae and 18 animals of similar age and sex served as controls. Hamsters were infected either with 50, 200, 300, 400 or 600 cercariae and sacrified after 8, 9, 10, 14, 18, 24 or 32 weeks. Infected and control hamsters were subjected to laboratory examinations including serum creatinine, serum albumin, total protein, serum cholesterol, total urine protein as well as histopathologic evaluations. Kidney biopsies were examined by light microscopy, indirect immunofluorescence and by electron microscopy. Significant proteinuria, hypoalbuminaemia and hypercholesterolaemia were observed in all but 5 S. haematobium-infected, but in none of the control hamsters. Renal impairment was observed in 5 hamsters. Histopathologic evaluations showed IgG, circulating anodic antigen and circulating cathodic antigen deposits in the renal glomeruli. By electron-microscopic examination, these deposits were seen mainly in the subendothelial, mesangial and paramesangial areas. Amyloid deposits were also seen in the renal glomeruli, tubular basement membrane and in the interstitium. A correlation was found between the extent of amyloid deposition and the duration but not the intensity of schistosomal infection. We have concluded that S. haematobium infection can lead to glomerulopathy in golden hamsters.

The prevalence of amyloid (A4) protein deposits within the cerebral and cerebellar cortex in Down's syndrome and Alzheimer's disease

The extent of amyloid deposition within the cerebellum and the cerebral cortex was assessed and compared, using anti-amyloid protein (A4) immunostaining and a novel methenamine silver method, in 20 patients aged between 60 and 77 years with Alzheimer's disease (AD), 29 patients aged between 13 and 71 years with Down's syndrome (DS), 26 demented patients with disorders other than AD and DS and in 20 non-demented elderly individuals of age range 60-102 years. In AD, amyloid deposits were noted in the cerebellar cortex in 90% of patients and in the meningeal vessels of the cerebellum in 80% of patients. In DS, amyloid deposits were seen in the cerebellar cortex in 82% of patients over 30 years of age and was universal in patients over 50 years of age. Overall, in DS, amyloid deposits were present in the meningeal vessels of the cerebellum in 79% of patients, but were present in 94% of those patients over 50 years of age. The sites of amyloid deposition in the cerebellar cortex were (poorly) detected by lectin histochemistry (Concanavalin A binding) in only 40% of patients with AD and 43% of all patients with DS (69% of those over 50 years of age). No amyloid deposits were seen in either the cerebellar cortex or its meningeal vessels in any of the 20 non-demented elderly individuals nor in any of the non-Alzheimer demented patients. The cerebellar amyloid deposits were never associated with a neuritic change [i.e. as characterised by the presence of (tau-positive) paired helical filaments (PHF)] and neurofibrillary tangles were seen only in a few cells of the dentate nucleus in a single patient with AD and in three of the elderly DS patients. Amyloid deposits were numerous in the cerebral cortex of all patients with AD and in all, except the 13-year-old patient, with DS. In all the AD patients and in most of the DS patients over 30 years of age, many of the cerebral cortical amyloid deposits were associated with neurites and were strongly recognised by lectin histochemistry. Amyloid deposits were present within the meningeal vessels of the cerebral cortex in 75% patients with AD and 72% of patients, over 30 years of age, with DS (82% of those over 50 years of age). These data indicate that the process of amyloidosis in AD and in elderly DS patients is not restricted to the cerebral cortex and may affect other grey matter regions, particularly the cerebellum.(ABSTRACT TRUNCATED AT 400 WORDS)

Clinical Significance of Histopathologic Patterns of Cardiac Amyloidosis

Cardiac amyloidosis may be asymptomatic or an important cause of progressive heart failure and refractory arrhythmia. To identify the morphologic markers of clinically significant cardiac amyloidosis, we analyzed the hearts of 47 patients with autopsy-proven cardiac amyloidosis (21 with primary amyloidosis [AL] and 26 with senile cardiac amyloidosis [SCA]) histologically for the extent and pattern of amyloid deposits. The extent of amyloid deposition was graded 1 through 4, corresponding with less than 10%, 10 to 25%, 26 to 50%, and more than 50% histologic involvement of the myocardium, respectively. The pattern of deposits was classified as nodular, perifiber, or mixed type, and the presence or absence of vascular involvement was determined. The hearts with primary amyloidosis showed predominantly high-grade deposits (76% grades 3 and 4), a perifiber (65%) or mixed (30%) pattern of deposits, and frequent (90%) vascular involvement. The hearts with senile cardiac amyloidosis tended to have low-grade deposits (62% grades 1 and 2), a nodular pattern (92%) of deposits, and infrequent (4%) vascular involvement. Clinically significant cardiac amyloidosis was associated with grade 2 or greater amyloid deposits in the heart and with involvement of intramyocardial arterioles.