Site Of Amyloid Deposition Research Articles

A systematic review of the literature on gastrointestinal tract amyloidomas: Presentation, management and outcomes.

e16220 Background: Gastrointestinal tract amyloidomas are uncommon malignancies, and little is known regarding this entity. AL amyloidosis and Amyloidomas mostly occurs in association to plasma cell dyscrasias such as multiple myeloma (MM), monoclonal gammopathy of undetermined significance (MGUS), and Waldenstrom’s macroglobulinemia (WM), although it has been also described in the absence of plasma cell dyscrasias. In general, plasma cell dyscrasias and systemic amyloidosis either AL or AA are typically treated with systemic therapy followed by Hematopoietic Stem Cell Transplant (HSCT) if patient is eligible. Nowadays, there are several systemic approaches that may or may not include autologous stem cell transplant. 56 On the contrary, localized amyloidomas have been mostly managed surgically and for the most part local amyloidomas are considered to have excellent prognosis. To this date there is no standard of care to guide clinicians in the management of local gastrointestinal amyloidomas. To the best of our knowledge this is the largest systematic review of gastrointestinal amyloidomas. The objective of this study was to evaluate the characteristics, treatments available, outcomes and surveillance these patients. Methods: We conducted a systematic review of cases reported in the literature from 1962-2021 that included a total of 62 cases reported in the literature. Patients with Gastrointestinal Amyloidomas reported in English literature were included in the analysis. We described and summarized the patient’s characteristics, treatments, clinical presentations, outcomes, and surveillance. Results: The systematic review of reported clinical cases included 62 patients. In these patients, the most common site of amyloid deposition was the stomach (45%). The median age of diagnosis is 64.4 years old, has a 2:1 prevalence among males (63%) to females (37%), abdominal pain is the most common type of presentation (41%) although patients could also be asymptomatic. There is a high curative rate (100%) with resection alone. Among patients treated with a type of systemic therapy, an 80% achieved a complete response. The minority of cases reported a type of surveillance post treatment and among those, the 62% pursued serial clinical evaluations alone. Conclusions: To our knowledge, this is the first and largest systematic review of the literature in Gastrointestinal Tract Amyloidomas. This is more common among males, and seems to have an excellent curative rate (100%) with surgery alone. Systemic therapy is an option for those with non-resectable amyloidomas. Serial clinical evaluations should be part of the standard surveillance care in these patients.

Extracardiac 18F-florbetapir imaging in patients with systemic amyloidosis: more than hearts and minds

Purpose18F-Florbetapir has been reported to show cardiac uptake in patients with systemic light-chain amyloidosis (AL). This study systematically assessed uptake of 18F-florbetapir in patients with proven systemic amyloidosis at sites outside the heart.MethodsSeventeen patients with proven cardiac amyloidosis underwent 18F-florbetapir PET/CT imaging, 15 with AL and 2 with transthyretin amyloidosis (ATTR). Three patients had repeat scans. All patients had protocolized assessment at the UK National Amyloidosis Centre including imaging with 123I-serum amyloid P component (SAP). 18F-Florbetapir images were assessed for areas of increased tracer accumulation and time–uptake curves in terms of standardized uptake values (SUVmean) were produced.ResultsAll 17 patients showed 18F-florbetapir uptake at one or more extracardiac sites. Uptake was seen in the spleen in 6 patients (35%; 6 of 9, 67%, with splenic involvement on 123I-SAP scintigraphy), in the fat in 11 (65%), in the tongue in 8 (47%), in the parotids in 8 (47%), in the masticatory muscles in 7 (41%), in the lungs in 3 (18%), and in the kidney in 2 (12%) on the late half-body images. The 18F-florbetapir spleen retention index (SRI) was calculated. SRI >0.045 had 100% sensitivity/sensitivity (in relation to 123I-SAP splenic uptake, the current standard) in detecting splenic amyloid on dynamic imaging and a sensitivity of 66.7% and a specificity of 100% on the late half-body images. Intense lung uptake was seen in three patients, one of whom had lung interstitial infiltration suggestive of amyloid deposition on previous high-resolution CT. Repeat imaging showed a stable appearance in all three patients suggesting no early impact of treatment response.Conclusion18F-Florbetapir PET/CT is a promising tool for the detection of extracardiac sites of amyloid deposition. The combination of uptake in the heart and uptake in the spleen on 18F-florbetapir PET/CT, a hallmark of AL, suggests that this tracer holds promise as a screening tool for AL.

Primary Systemic Amyloidosis with Unusual Dermatological Manifestations: A Rare Case Report.

Amyloidosis is a group of heterogeneous diseases characterized by pathological deposition of proteinaceous substance extracellularly in various tissues. The clinical presentation depends on the site of amyloid deposition, with predominant involvement of mesenchymal elements and cutaneous findings in 30–40% of patients in case of primary systemic amyloidosis. We present a case of idiopathic primary systemic amyloidosis presenting with an unusual finding of nodulo-ulcerative lesion over tongue along with multiple skin-colored nodules, mimicking squamous cell carcinoma of tongue with secondary cutaneous metastasis, as well as lacking the classical presentation of purpura, macroglossia, waxy papules, and plaques.

Proliferation in the Alzheimer Hippocampus Is due to Microglia, Not Astroglia, and Occurs at Sites of Amyloid Deposition

Microglia and astrocytes contribute to Alzheimer's disease (AD) etiology and may mediate early neuroinflammatory responses. Despite their possible role in disease progression and despite the fact that they can respond to amyloid deposition in model systems, little is known about whether astro- or microglia can undergo proliferation in AD and whether this is related to the clinical symptoms or to local neuropathological changes. Previously, proliferation was found to be increased in glia-rich regions of the presenile hippocampus. Since their phenotype was unknown, we here used two novel triple-immunohistochemical protocols to study proliferation in astro- or microglia in relation to amyloid pathology. We selected different age-matched cohorts to study whether proliferative changes relate to clinical severity or to neuropathological changes. Proliferating cells were found across the hippocampus but never in mature neurons or astrocytes. Almost all proliferating cells were colabeled with Iba1+, indicating that particularly microglia contribute to proliferation in AD. Proliferating Iba1+ cells was specifically seen within the borders of amyloid plaques, indicative of an active involvement in, or response to, plaque accumulation. Thus, consistent with animal studies, proliferation in the AD hippocampus is due to microglia, occurs in close proximity of plaque pathology, and may contribute to the neuroinflammation common in AD.

Benefit of doxycycline treatment on articular disability caused by dialysis related amyloidosis

Doxycycline inhibits amyloid formation in vitro and its therapeutic efficacy is under evaluation in clinical trials for different protein conformational diseases, including prion diseases, Alzheimer’s disease and transthyretin amyloidosis. In patients on chronic hemodialysis, a persistently high concentration of β2-microglobulin causes a form of amyloidosis (dialysis-related amyloidosis, DRA) localized in bones and ligaments. Since doxycycline inhibits β2-microglobulin fibrillogenesis in vitro and accumulates in bones, DRA represents an ideal form of amyloidosis where doxycycline may reach a therapeutic concentration at the site of amyloid deposition. Three patients on long-term dialysis with severe articular impairment and uncontrollable pain due to DRA were treated with 100 mg of doxycycline daily. Pharmacokinetics and safety of treatment were conducted. Plasmatic levels of the drug reached a plateau after one week (1.1–2.3 µg/ml). Treatment was well tolerated in two patients for a year, while one was suspended after 5 months due to mild esophagitis. Treatment was associated with a significant reduction in articular pain and with a significant and measurable improvement in passive and active movements in all cases, despite the persistence of unchanged amyloid deposits measured by magnetic resonance imaging.

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.

Responses to Amyloids of Microbial and Host Origin Are Mediated through Toll-like Receptor 2

Curli fibrils are proteinaceous bacterial structures formed by amyloid fibrils composed of the major curli subunit CsgA. Like beta-amyloid 1-42, which is associated with brain inflammation and Alzheimer's disease, curli fibrils have been implicated in the induction of host inflammatory responses. However, the underlying mechanisms of amyloid-induced inflammation are not fully understood. In a mouse sepsis model, we show that curli fibrils contributed to Nos2 expression, a hallmark of inflammation, by stimulating Toll-like receptor (TLR) 2. The TLR2 agonist activity was reduced by an amyloidogenicity-lowering amino acid substitution (N122A) in CsgA. Amyloid-forming synthetic peptides corresponding to beta-amyloid 1-42 or CsgA 111-151 stimulated Nos2 production in macrophages and microglia cells through a TLR2-dependent mechanism. This activity was abrogated when an N122A substitution was introduced into the synthetic CsgA peptide. The induction of TLR2-mediated responses by bacterial and eukaryotic amyloids may explain the inflammation associated with amyloids and the resulting pathologies.

Novel approaches for immunotherapeutic intervention in Alzheimer's disease

Immunotherapy can attenuate amyloid neuropathology and improve cognitive function in transgenic models of Alzheimer's disease. However, the first clinical trial was halted when 6% of the Alzheimer's patients developed aseptic meningoencephalitis. Postmortem analysis of two cases with meningoencephalitis showed robust glial activation, T-cell infiltration and sporadic clearance of Aβ. Interestingly, transgenic mouse models of Alzheimer's disease failed as predictors of these adverse inflammatory events. However there are now several studies with amyloid precursor protein transgenic mice that have reported an increased risk of microhemorrhages at sites of cerebrovascular amyloid deposits and because approximately 80% of Alzheimer's patient's have cerebrovascular pathology, there is concern regarding clinical trials using passive administration of humanized anti-Aβ antibodies. Although many studies have now been published on immunotherapy in mouse models, the mechanism(s) of antibody-mediated clearance of β-amyloid from the brain, and the cause of the antibody-induced microhemorrhages remain unclear. In this review, we will discuss the most recent results from the first clinical trial, offer speculation on possible causes for the failure of the trial, review data on antibody-mediated clearance mechanisms, explore the role of complement and inflammation in the clearance of β-amyloid, and suggest novel strategies for avoiding problems in future clinical trials. The central hypothesis being proposed in this review is that anti-Aβ antibodies delivered directly to the CNS at the sites of amyloid deposits will be far more effective at clearing Aβ and safer than active or passive immunization strategies where the majority of the antibodies are in the periphery.

Cleavage of AL amyloid proteins and AL amyloid deposits by cathepsins B, K, and L.

Cathepsin (Cath) B, CathK and CathL are cysteine proteases that participate in the lysosomal protein degradation system and are expressed in macrophages, epithelioid cells, and multinucleated histiocytic giant cells (MGCs). Both macrophages and MGCs are commonly found adjacent to immunoglobulin light chain-associated (AL) amyloid deposits, which raised the question of whether cysteine proteases are able to cleave AL amyloid proteins and AL amyloid deposits. The present study has investigated whether recombinant human CathB, CathK, and CathL are able to degrade AL(VlambdaVI) amyloid proteins and AL amyloid deposits. Using immunohistochemistry, CathB, CathK, and CathL were found adjacent to AL amyloid deposits. In vitro degradation experiments using purified AL amyloid proteins showed that CathB, CathK, and CathL degrade AL(VlambdaVI) amyloid proteins. Furthermore, using unfixed tissue sections from an amyloidotic spleen as an in vitro model for extracellular proteolysis of intact amyloid deposits, it was demonstrated that all three cysteine proteases are also capable of degrading AL amyloid in situ. This is the first study to show that cysteine proteases are able to cleave AL amyloid proteins. However, the efficiency with which proteolysis occurs depends on the concentration of active protease recruited at the sites of amyloid deposition, and possibly on the structure of the AL amyloid proteins.

Affinity Binding of Glycosaminoglycans with β2-Microglobulin

Background: A constant finding in β₂-microglobulin (β2m) amyloidosis is an increase in tissue heparan sulfate (HS) and chondroitin sulfate (CS) proteoglycans (PGs) at sites of amyloid deposits. However, the binding characteristics of PGs with β2m have not been elucidated yet. Methods: Using affinity retardation chromatography, β2m- and glycosaminoglycan (GAG)-anchored columns, an affinity between β2m and GAGs was analyzed. Five peptides which spanned the entire β2m amino acid sequence were prepared, and an affinity between these peptides and heparin (HP) was examined. Furthermore, the specific binding of biotinylated β2m peptide for AA amyloid deposits via GAGs was examined on tissue sections. Results: Using β2m-anchored column, HP showed the smallest dissociation constant (K_d), i.e. the strongest affinity, among the GAGs examined. At 0.4 M NaCl, the K_ds of β2m relative to BSA-anchored columns for HP, HS, CS-A, CS-B, and CS-C were 94, 620, 130, 660 and 190 µM, respectively. Using GAG-anchored columns, at 0.15 M NaCl, pH 7.4, β2m also showed an affinity for HP, with the K_d relative to a reference column being 370 µM. Under the latter conditions, no β2m affinity for CSA was demonstrated. Among the five peptides, peptide-1, which is composed of residues 1–24, showed the highest affinity for HP, the K_d being 190 µM. Peptides analogous to peptide-1, in which each basic amino acid was individually replaced by alanine, showed a remarkable decrease in affinity for HP. The specific binding of biotinylated β2m peptide for AA amyloid deposits via HS and CS was confirmed in situ by pretreatment with heparitinase and chondroitinase ABC. Conclusion: The present data indicate that HP/HS is effective in the binding of the β2m monomer, and the anatomic localization of β2m amyloid precursor protein.

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.

Pathogenesis of beta2-microglobulin amyloidosis.

Hemodialysis-related amyloidosis is a relatively new form of systemic amyloidosis, with beta2-microglobulin (B2M) being identified as the major constituent protein. Most of the clinical findings are related to amyloid deposition in osseo-articular tissues. B2M amyloid deposits first appear in the cervical intervertebral discs, which are well known to be susceptible to mechanical stress. A close relationship between changes of microenvironment caused by such stress and amyloid deposition is highly suggested. In advanced cases, an inflammatory reaction composed of macrophages, multinucleated giant cells, and granulation tissue, is observed around the amyloid deposits. Purified amyloid protein is native B2M, and mutations and proteolysis are not believed to be important for its deposition. Plasma levels of B2M are elevated as much as 5-10 times because of the inability of hemodialysis equipment removal of B2M from blood plasma, the duration being very important for B2M amyloid fibrillogenesis. Heparan sulfate proteoglycans, perlecan, is increased at the same sites of amyloid deposits from the early stages. In B2M amyloidosis, an increase of heparan sulfate proteoglycans is observed in the vascular wall and synovium, but in the discs, ligaments and cartilage, there is an increase of chondroitin sulfate proteoglycans predominantly. B2M has an affinity for heparan sulfate proteoglycans, although it is weaker than that for laminin and type IV collagen. This is related to the interactions between negative charges of sulfate groups of proteoglycans and positive charges of basic amino acids in N-terminal side of B2M. Increased cytokines production in the synovium, induced by advanced glycation end products as well as elevated plasma levels, is also linked to inflammatory reactions. Increased expression of matrix metalloproteinases (MMP), especially MMP-1 and -9, is related to the destructive changes of the bone and cartilage. The decrease of plasma levels by high flux membrane and control of inflammatory reactions are very important for prevention of B2M amyloidosis.

Amylose secondaire : une complication sévère de la spondylarthrite ankylosante. À propos de deux cas

Study objective. To report two cases of amyloidosis secondary to ankylosing spondylitis. Patients and Results. Of the 47 ankylosing spondylitis patients who have received follow-up at our department over the last few years, two have developed AA amyloidosis. Both have extremely severe, long-standing joint disease, with virtually complete spinal ankylosis and destructive peripheral arthritis of the hips and wrists; one also has tarsal joint destruction. Renal dysfunction was the first manifestation of amyloidosis in both cases. One patient required chronic hemodialysis and developed peritonitis due to colonic perforation, probably at a site of amyloid deposition. Conclusions. Secondary amyloidosis is a rare complication of ankylosing spondylitis that can cause severe renal and gastrointestinal complications. No treatment capable of clearing established amyloid deposits is available to date.

Cytokines Associated with Amyloid Plaques in Alzheimer's Disease Brain Stimulate Human Glial and Neuronal Cell Cultures to Secrete Early Complement Proteins, But Not C1-Inhibitor

Complement activation products C1q, C4c/d, and C3c/d in amyloid plaques in Alzheimer's disease probably result from direct binding and activation of C1 by amyloid β peptides. RT-PCR and in situ hybridization studies have shown that several complement factors are produced in the brain parenchyma. In the present study, cytokines that can be detected in amyloid plaques (i.e., interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-α) were found to differentially stimulate the expression of C1 subcomponents, C1-Inhibitor (C1-Inh), C4, and C3, by astrocyte and microglial cell cultures derived from postmortem adult, human brain specimens and by neuroblastoma cell lines in culture. C1r and C1s were secreted at low levels by astrocytes and neuroblastoma cell lines. Exposure of cells to IL-1α, IL-1β, TNF-α and to a far lesser extent IL-6, markedly upregulated C1r, C1s, and C3 production. C4 synthesis increased in response to interferon (IFN)-γ and IL-6, whereas that of C1-Inh could be stimulated only by IFN-γ. Thus, C1-Inh production is refractory to stimulation by plaque-associated cytokines, whereas these cytokines do stimulate C1r, C1s, and also C4 and C3 secretion by astrocytes and neuronal cells in culture. In contrast to the amyloid plaque associated cytokines IL-1β, IL-1α, and TNF-α, the amyloid peptide Aβ1–42 itself did not stimulate C1r and C1s synthesis by astrocytes, microglial cells, or neuroblastoma cell lines. Microglial cells were the only cell type that constitutively expressed C1q. The ability of C1q to reassociate with newly formed C1r and C1s upon activation of C1 and subsequent inactivation by C1-Inh, may enable ongoing complement activation at sites of amyloid deposition, especially when C1-Inh is consumed and not replaced.

Amyloidosis associated with long-term dialysis

Dialysis amyloidosis is a frequent complication encountered in patients receiving long-term hemodialysis. These amyloid deposits are composed mainly of an insoluble fibrillar material that consists of beta 2-microglobulin (beta 2-m). While this fibrillar protein is a major component of these deposits, numerous other substances have been identified in the amyloid deposits; e.g., amyloid P component, calcium, glycosaminoglycans, chondroitin sulfate, hyaluronic acid, collagen, protease inhibitors, k-chain protein, ubiquitin, apolipoprotein E and macrophages. Hypotheses on the pathogenesis of amyloidosis have suggested roles for each of these factors. The pathogenesis of beta 2-m-related amyloidosis is probably multifactorial, with the retention of beta 2-m presumed to be the basic requirement for its initiation. It has been demonstrated in vivo that radiolabeled beta 2-m accumulates at the site of amyloid deposits. Our autoradiographic study of synovial tissue demonstrated that the cells had taken up radiolabeled beta 2-m, indicating that circulating radiolabeled-beta 2-m could be detected as an accumulation because it is taken up by the cells around the amyloid deposits. At present it can not be said that any basic treatment for beta 2-m-related amyloidosis has been established. It has been reported that the administration of a low dose of a corticosteroid may be effective in treating beta 2-m amyloid-related arthropathy. The articular symptoms resolved in most patients with corticosteroid. However, it should be borne in mind that corticosteroid may induce some adverse effects. Corticosteroid should be used only in patients with severe articular symptoms.

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)

Antisera to an amino-terminal peptide detect the amyloid protein precursor of alzheimer's disease and recognize senile plaques

The cerebral amyloid deposited in Alzheimer's disease (AD) contains a 4.2 kDa beta amyloid polypeptide (beta AP) that is derived from a larger beta amyloid protein precursor (beta APP). Three beta APP mRNAs encoding proteins of 695, 751, and 770 amino acids have previously been identified. In each of these, there is a single membrane-spanning domain close to the carboxyl-terminus of the beta APP, and the 42 amino acid beta AP sequence extends from within the membrane-spanning domain into the large extracellular region of the beta APP. We raised rabbit antisera to a peptide corresponding to amino acids 45-62 near the amino-terminus of the beta APP. We show that these antisera detect the beta APP by demonstrating that they (i) label a set of approximately 120 kDa membrane-associated proteins in human brain previously detected by antisera to the carboxyl-terminus of beta APP and (ii) label a set of approximately 120 kDa membrane-associated proteins that are selectively overexpressed in cells transfected with a full length beta APP expression construct. The beta APP45-62 antisera specifically stain senile plaques in AD brains. This finding, along with the previous demonstration that antisera to the carboxyl-terminus of the beta APP label senile plaques, indicates that both near amino-terminal and carboxyl-terminal domains of the beta APP are present in senile plaques and suggests that proteolytic processing of the full length beta APP molecule into insoluble amyloid fibrils occurs in a highly localized fashion at the sites of amyloid deposition in AD brains.

Amyloid-enhancing factor (AEF) in the pathogenesis of AA-amyloidosis in the hamster.

AA-amyloidosis was induced in hamsters receiving amyloid-enhancing factor (AEF) by daily subcutaneous injection with either an aged casein solution or casein supplemented with lipopolysaccharide (LPS). Both amyloid inducers gave similar results with respect to amyloid development in spleen, liver and kidneys and to serum amyloid A (SAA) concentrations and plasma cathepsin D activities. AEF was isolated from amyloid-containing tissue by the method described by Hol et al. (1985), and amyloid-enhancing material was also extracted from isolated hamster amyloid fibrils by intensive sonification. This fibril-derived amyloid-enhancing material lacked typical green birefringence after staining with Congo red and appeared as amorphous material on electron microscopy. AEF shortened the pre-amyloid phase for splenic and hepatic amyloid development and also the subsequent interval before renal amyloid deposition. This indicates that endogenous AEF, unlike passively transferred preformed AEF, is not distributed throughout the body and is probably generated at the site of amyloid deposition. Moreover, these results suggest that amyloid deposition in the kidneys, like that in the spleen and liver, involves an AEF-dependent pathway. Thus redistribution of amyloid is probably not an important cause of renal amyloid involvement. In addition to the reduction in the lag phase for splenic and hepatic amyloid deposition, AEF also speeds the changes in SAA concentration and plasma cathepsin D activity. This indicates that AEF accelerates rather than eliminates the pre-amyloid phase.

Renal amyloidosis. Evaluation by gallium imaging.

A study has been performed to evaluate the efficacy of gallium imaging in the detection of renal amyloidosis. Ten of the 11 patients who had biopsy-proven renal amyloidosis demonstrated marked uptake in both kidneys. One patient revealed moderate gallium uptake in his kidneys. None of the patients had underlying renal or extrarenal pathology other than amyloidosis, which could account for renal gallium uptake (renal infection, neoplasm, hepatic failure or frequent blood transfusions). Four patients also had extrarenal foci of abnormal gallium uptake, suggesting other sites of amyloid deposits. Our data strongly suggest that gallium imaging has a high sensitivity for detection of renal amyloidosis. Its specificity is enhanced significantly by careful review of the clinical history to exclude other known causes of renal gallium uptake. Potentially, gallium imaging may be used to monitor the progress of patients under experimental therapy.

Bleeding Manifestations in Patients With Amyloidosis

To the Editor.— Yood and colleagues, in a recent article inThe Journal(1983;249:1322), suggest that bleeding problems in patients with amyloidosis are probably more closely related to increased fragility of amyloid-infiltrated blood vessels than to abnormal coagulation. We would like to add, in support of their suggestion, that a localized form of amyloidosis within the CNS, cerebral amyloid angiopathy (CAA), is also associated with a bleeding tendency, apparently as a result of structural alterations in vessel walls. Cerebral amyloid angiopathy typically occurs in localized fashion within the brains of nonhypertensive elderly subjects and is characterized clinically by dementia and recurrent episodes of intracerebral hemorrhage. 1-3 The distribution of lesions correlates closely with sites of amyloid deposition within the brain, namely, small leptomeningeal and superficial cortical arteries and veins. The sharp localization of microscopic hemorrhages of varying age that we and others 2 have observed around vessels heavily infiltrated by