Extensive Amyloid Deposition Research Articles

Selective Anterior Cerebral Amyloid Angiopathy and Frontal Lobe Dementia: A Clinicopathologic Correlation

A 77 year old white male with a frontal lobe type of dementia was found to have at autopsy extensive deposition of amyloid in the leptomeningeal blood vessels of the frontal lobe, and to a much lesser degree in the parietal lobe and hippocampus. The temporal and occipital lobes where almost free of amyloid. Parenchymal blood vessels were much less affected. Other striking features included cortical gliosis in the frontal lobe, and the scarcity of amyloid plaques. Neurofibrillary tangles were very rarely encountered in the hippocampus. The dementia could not be fully explained on the basis of Alzheimer's disease, alcohol-related damages or cerebral infarctions. The selective frontal amyloid angiopathy and gliosis may have been related to the dementia.

Primary plasmacytoma of lymph nodes

Primary plasmacytoma of the lymph nodes is very rare, and there are fewer than 20 reported cases. These cases appeared to have a better prognosis than other extramedullary plasmacytomas, with rare recurrence and no progression to myeloma after treatment. To better characterize the clinicopathological features and the pathogenesis of primary plasmacytoma of the lymph nodes, we reviewed our consultation files and retrieved seven such cases. The age of presentation ranged from 39 to 76 years (median age, 59 years), with three women and four men. The clinical follow-up varied from 1 to 14 years. All patients presented with enlarged lymph nodes and had an indolent clinical course, except for one patient with slow progression and increasing numbers of bone marrow plasma cells. Five patients were treated with excision only and two with excision and chemotherapy. None of the patients had recurrence or developed multiple myeloma. All cases showed immunoglobulin light chain restriction, four with monotypic lambda and three with monotypic kappa. One patient had extensive nodal amyloid deposition. Four cases had monoclonal heavy chain expression, three with monoclonal immunoglobulin (Ig) G and one with monoclonal IgM. All cases were negative for CD20 and CD43, and six cases expressed CD79a. Overexpression of p53 and bcl-2 was not detected by immunostaining in any of the cases. Epstein-Barr viral (EBV) RNA was not detected in all seven cases by in situ hybridization, and no Kaposi's sarcoma—associated herpesvirus (KSHV) DNA sequences were detected by polymerase chain reaction in five cases. Our results confirm a more favorable outcome and rare progression to multiple myeloma in primary nodal plasmacytomas after excision or chemotherapy. The results of oncoprotein and viral studies suggest that the pathogenesis of primary nodal plasmacytoma may not be due to bcl-2- and p53-associated changes or viral-induced changes by EBV and KSHV.

Intestinal pseudo-obstructive paralytic ileus and colonic bleeding due to myeloma-related (AL) amyloidosis

An autopsy case of a 57-year-old man with multiple myeloma (IgA lambda light chain) who developed chronic intestinal pseudo-obstruction and bleeding associated with gastrointestinal amyloidosis over three and a half years is reported Nine doses of cyclic therapy with VMCP (vincristine, melphalan, cyclophosphamide and prednisone) put the patient into partial remission. This was followed by maintenance therapy with MP (melphalan and prednisone) but levels of Bence Jones protein increased progressively. Subsequently, combination therapy of both alpha-interferon (αIFN) with VP (vincristine and prednisone) caused a decrease in Bence Jones protein. After 2 years, scrota1 tongue, abdominal distention and constipation appeared. A rectal biopsy was positive for amyloidosis. Gradually, paralytic ileus developed due to both extensive amyloid deposition in the digestive tract and a neurologic disorder as a side effect of the vincristine treatment. Six months after biopsy bleeding from multiple colonic ulcers associated with the vascular amyloid and ischemia caused the patient's death.

Islet amyloid formation associated with hyperglycemia in transgenic mice with pancreatic beta cell expression of human islet amyloid polypeptide.

Pancreatic islet amyloid deposits are a characteristic pathologic feature of non-insulin-dependent diabetes mellitus and contain islet amyloid polypeptide (IAPP; amylin). We used transgenic mice that express human IAPP in pancreatic beta cells to explore the potential role of islet amyloid in the pathogenesis of non-insulin-dependent diabetes mellitus. Extensive amyloid deposits were observed in the pancreatic islets of approximately 80% of male transgenic mice > 13 months of age. Islet amyloid deposits were rarely observed in female transgenic mice (11%) and were never seen in nontransgenic animals. Ultrastructural analysis revealed that these deposits were composed of human IAPP-immunoreactive fibrils that accumulated between beta cells and islet capillaries. Strikingly, approximately half of the mice with islet amyloid deposits were hyperglycemic (plasma glucose > 11 mM). In younger (6- to 9-month-old) male transgenic mice, islet amyloid deposits were less commonly observed but were always associated with severe hyperglycemia (plasma glucose > 22 mM). These data indicate that expression of human IAPP in beta cells predisposes male mice to the development of islet amyloid and hyperglycemia. The frequent concordance of islet amyloid with hyperglycemia in these mice suggests an interdependence of these two conditions and supports the hypothesis that islet amyloid may play a role in the development of hyperglycemia.

Dialysis-Related Amyloidosis Manifested as Masses in the Buttocks

A 40-year-old man had enlarging painful gluteal masses that developed after 17 years of hemodialysis. Pathologic examination revealed extensive deposition of beta 2-microglobulin amyloid. A bladder biopsy done during evaluation for possible transplantation also showed amyloid deposits. This constellation of findings has not been reported in a patient with beta 2-microglobulin amyloidosis. Patients with dialysis-related amyloidosis should be carefully assessed for systemic involvement. Renal transplantation may prevent further amyloid deposition and provide relief of pain.

Pathogenesis of Feline Diabetes Mellitus

Cats are one of the few species that develop a form of diabetes mellitus that is clinically and histologically analogous to human type 2 diabetes mellitus. Figure 9 summarizes the etiologic factors thought to be involved in the development of feline and human type 2 diabetes. The main metabolic characteristics of type 2 diabetes mellitus are impaired insulin secretion and resistance to the action of insulin in its target tissues. Impaired beta cell function occurs before histologic changes become evident. The characteristic histologic finding in cats with type 2 diabetes is deposition of amyloid in pancreatic islets. Amyloid deposition occurs before the onset of clinical signs, but does not seem to be the primary defect. Pancreatic amyloid is derived form the recently discovered pancreatic hormone amylin. Amylin is synthesized in pancreatic beta cells, and is co-stored and co-secreted with insulin. Amylin has been postulated to be involved in the pathogenesis of feline diabetes mellitus both through its metabolic effects, which include inhibition of insulin secretion and induction of insulin resistance, and via progressive amyloid deposition and beta cell degeneration. Increased amylin concentration has been documented intracellularly in cats with impaired glucose tolerance and in the plasma of diabetic cats, and supports the hypothesis that amylin is involved in the pathogenesis of type 2 diabetes. Obesity is a common finding in diabetic felines and is a contributing factor to the insulin resistance present in type 2 diabetes. Clinical signs of diabetes develop once total insulin secretion decreases to 20% to 25% of normal levels. Many diabetic cats have been treated successfully with oral hypoglycemics, but 50% to 70% of diabetic cats are insulin dependent. Based on histologic evidence, this is the result of extensive amyloid deposition and subsequent beta cell degeneration, rather than autoimmune destruction of pancreatic beta cells associated with type 1 diabetes. Alternative ways of treating type 2 diabetes currently are being investigated. Amylin antagonists recently have been proposed as a novel treatment to reverse the deleterious effects of excessive amylin concentrations. The gastrointestinal hormone glucagon-like peptide-1 may also prove useful in treating diabetic cats, because of its stimulatory effect on insulin secretion and synthesis, and the absence of significant hypoglycemic effect.

Gastrointestinal amyloidosis: radiologic features by chemical types.

To determine the correlation between the radiographic and histologic findings of amyloidosis according to chemical type of amyloid protein. The 49 patients with amyloidosis were examined radiographically, and gastrointestinal tract biopsy specimens were studied histologically. Considerable differences were found between amyloid proteins. On immunohistochemical studies, amyloid A produced a coarse mucosal pattern with innumerable fine granular elevations, which reflected expansion of the lamina propria by amyloid deposits. Polypoid protrusions and invariable thickening of the folds were evident only in light chain protein, correlating with massive amyloid deposits in the muscularis mucosae and submucosa. beta 2-Microglobulin produced marked delay in transit time and dilatation of the small and large intestines, relating to extensive amyloid deposits in the muscularis propria. The prevalence of these radiographic changes was highest in the small intestine for every chemical type. Characteristic radiographic changes of each chemical type of amyloid protein can be detected well in the small intestine.

Iodine-123-labelled serum amyloid P component scintigraphy in amyloidosis.

This study describes the results of scintigraphy with iodine-123-labelled serum amyloid P component (SAP) as a means of establishing the distribution of organ involvement in amyloidosis. The significance of 123I-SAP scans obtained in 15 patients with biopsy-proven AA or AL amyloidosis is discussed. Biopsy-proven amyloidosis was typically confirmed by scintigraphy, though such confirmation was not obtained in the kidneys in six patients with histological proof of extensive renal amyloid deposition. This lack of uptake may have been due to the accumulation of a major part of the 123I-SAP in the spleen and/or liver. Twenty-four hour whole-body retention of 123I-SAP was higher in patients with amyloidosis than in controls. Twenty-four hour tracer accumulation of the radioactivity in the extravascular compartment was notably greater in patients than in controls and appeared to be a good diagnostic criterion. We conclude that 123I-SAP scintigraphy may be helpful for the evaluation of organ involvement not only in patients with biopsy-proven amyloidosis but also when a biopsy cannot be performed or when a strong suspicion of amyloidosis exists in spite of repeated negative biopsies.

Acute phase proteins but not activated microglial cells are present in parenchymal beta/A4 deposits in the brains of patients with hereditary cerebral hemorrhage with amyloidosis-Dutch type.

With immunohistochemical staining methods on cryostat sections we investigated the brains of three patients with hereditary cerebral hemorrhage with amyloidosis-Dutch type, one of the cerebral beta/A4 amyloid diseases. Immunostaining for beta/A4 protein revealed numerous non-fibrillar beta/A4 depositions (amorphous or diffuse plaques) in the brain parenchyma in addition to extensive vascular amyloid deposition. All amorphous plaques contain complement proteins and alpha 1-antichymotrypsin but activated microglial cells expressing major histocompatibility (MHC) class II antigens HLA-DR and leucocyte adhesion molecules belonging to the lymphocyte-function-associated antigen (LFA)-1 family are virtually absent in cortical gray matter. Our findings are discussed from the view that a cascade of events including acute phase proteins and activated microglial cells are involved in classical amyloid plaque formation.

Pathologic Fracture Associated With Amyloid Deposition in the Bone of a Chronic Hemodialysis Patient

A 63-year-old male who had been on hemodialysis for 14 years developed extensive amyloid deposition in the femoral head and neck that, after a fall, resulted in a femoral neck fracture. The plasma level of beta 2-microglobulin in this patient was elevated, and bone specimens from the fracture site demonstrated positive Congo-red staining, suggesting an association with amyloid deposition.

Hereditary Cerebral Hemorrhage with Amyloidosis—Dutch Type: A Congophilic Angiopathy

Hereditary cerebral hemorrhage with amyloidosis--Dutch type (HCHWA-D) is characterized by recurrent cerebral hemorrhages and dementia at a relatively young age. The symptoms are caused by extensive deposition of amyloid in cerebral arterioles and leptomeningeal arteries. A point-mutation in the beta-protein precursor gene on chromosome 21 is the underlying cause of the disease. This paper summarizes the clinical, radiologic, pathologic, and genetic features of this disease, with special attention to the relation between HCHWA-D and Alzheimer's disease, which is also characterized by beta-protein deposition.

Generalized amyloidosis from β2-microglobulin, with caecal perforation after long-term haemodialysis

A 73-year-old man with chronic renal failure of undetermined aetiology had received haemodialysis for 12 years when he died of acute purulent peritonitis due to caecal perforation. Amyloid deposits detected in a cystic bone lesion in the left hip had caused a pathological fracture 17 days before death. At autopsy, extensive amyloid deposits were found in the osteoarticular system, in the cartilaginous surface and the capsular tissue of joints, ligaments, vertebral discs and bone. In addition, vascular amyloid deposits were diagnosed in the heart, kidneys, testes, lungs, skin and in the gastrointestinal tract. A special feature of this case were interstitial amyloid deposits forming a fine-meshed structure in the myocardium and plate-like deposits in the gastrointestinal tract. Immunohistochemically, all these deposits reacted strongly with antibody to human beta 2-microglobulin but showed no reaction with antibodies to AA, A-lambda, A-kappa and AF. The present case demonstrates that extra-osteoarticular manifestations of AB-amyloidosis can cause serious complications.

Parenchymal preamyloid and amyloid deposits in the brains of patients with hereditary cerebral hemorrhage with amyloidosis—Dutch type

Hereditary cerebral hermorrhage with amyloidosis—Dutch type, one of the ‘cerebral β-amyloid diseases’, like Alzheimer's disease, is characterized by extensive deposition of amyloid in small cerebral vessels. We investigated the presence of parenchymal β-protein deposits in two Dutch patients with hereditary cerebral hemorrhage with amyloidosis. Immunostaining with anti-SP28 revealed a full spectrum of these deposits, varying from preamyloid deposits to burned-out plaques. However, their density is less than in Alzheimer's desease, and immunostaining with Alz50 and anti-PHF did not show abnormal neurites in and around amyloid deposits in these two patients.

Left ventricular free wall rupture following acute myocardial infarction and cardiac amyloid

A 74-year-old man died of left ventricular free wall rupture 6 days following an acute inferoposterior wall myocardial infarction. His hospital course was complicated by pump failure which proved resistant to inotropic support, diuresis, and percutaneous transluminal coronary angioplasty. At necropsy, extensive amyloid deposition was noted. This case constitutes an unusual clinical setting for myocardial rupture because of the severity of systolic left ventricular dysfunction as well as cardiac amyloidosis.

Amyloid β Protein Precursor Gene and Hereditary Cerebral Hemorrhage with Amyloidosis (Dutch)

Human hereditary cerebral hemorrhage with amyloidosis of the Dutch type (HCHWA-D), an autosomal dominant form of cerebral amyloid angiopathy (CAA), is characterized by extensive amyloid deposition in the small leptomeningeal arteries and cortical arterioles, which lead to an early death of those afflicted in their fifth or sixth decade. Immunohistochemical and biochemical studies have indicated that the amyloid subunit in HCHWA-D is antigenically related to and homologous in sequence with the amyloid beta protein isolated from brains of patients with Alzheimer's disease and Down syndrome. The amyloid beta protein is encoded by the amyloid beta protein precursor (APP) gene located on chromosome 21. Restriction fragment length polymorphisms detected by the APP gene were used to examine whether this gene is a candidate for the genetic defect in HCHWA-D. The data indicate that the APP gene is tightly linked to HCHWA-D and therefore, in contrast to familial Alzheimer's disease, cannot be excluded as the site of mutation in HCHWA-D.

Behcet's Disease with Renal Amyloidosis: Report of a Case from Jordan with Review of the Literature

Behcet's Disease with Renal Amyloidosis: Report of a Case from Jordan with Review of the Literature

Infarction of intestine with massive amyloid deposition in two patients on long-term hemodialysis

Two patients undergoing hemodialysis for 19 and 13 yr, respectively, developed intestinal infarction with extensive amyloid deposits in the muscle layer and blood vessels. In 1 patient the deposit reacted positively with antiserum to β2-microglobulin by immunohistochemical stain, and therefore was classified as β2-microglobulin in origin. The amyloid protein of the other patient remains unclassified. In patients with gastrointestinal symptoms who have been undergoing hemodialysis for long periods of time, amyloidosis of the intestine should be considered.

Amyloidosis

The clinical amyloidosis syndromes are a heterogeneous group of disorders characterised by abnormal extracellular accumulation of autologous protein material. Amyloid deposits are largely composed of insoluble protein fibrils which are intimately associated with sulphated glycosaminoglycan residues. Amyloid P component (AP) is a minor but almost universal constituent of the deposits and is derived from the normal circulating glycoprotein serum amyloid P component (SAP), a member of the pentraxin family of plasma proteins. The current classification of amyloidosis is based on the chemical nature of the fibril protein subunits. Systemic amyloidosis is well known as a relatively rare but important cause of serious morbidity, and vital organ involvement is usually fatal. In recent years it has become increasingly recognised that amyloid deposition in a variety of sites is a universal feature of ageing, and in particular that amyloid in the cerebral blood vessels and within the brain itself is an integral part of the pathology of Alzheimer's disease. Also recently, a new form of amyloid has emerged, confined to patients who have received long term haemodialysis for end stage renal failure, in whom β 2-microglobulin ( β 2M) is laid down as amyloid fibrils predominantly in periarticular and bony tissues. Considerable progress in knowledge of the composition, molecular structure and properties of many different constituents of amyloid has been made in the past 30 years. However, the precise mechanisms of amyloid fibril formation, deposition and persistence are not known and no generally effective therapy yet exists which can arrest amyloid deposition or promote its resolution. A major reason for our ignorance of the natural history of amyloidosis is that it is an exclusively histological diagnosis, at the time of which most patients with systemic disease have extensive amyloid deposits throughout many organs and a very poor prognosis. Some optimism has been generated from recent work suggesting that amyloid fibrils are not inherently non-biodegradable and that the use of radiolabelled SAP may permit non-invasive sensitive, scintigraphic imaging of amyloid deposits in vivo.

Vagus nerve and celiac ganglion lesions in generalized amyloidosis: A correlative study of familial amyloid polyneuropathy and AL-amyloidosis

To clarify the cause of gastrointestinal disorders in systemic amyloidosis we made pathologic and morphometric studies of vagus nerves, celiac ganglia, stomach and rectum in three autopsied cases with type 1 familial amyloid polyneuropathy (FAP) and two with nonhereditary generalized amyloidosis (AL-amyloidosis). The gastric and rectal walls in all cases were affected in the same way by amyloid deposition. On the other hand, there was a great difference between the two diseases in the severity of vagus nerve and celiac ganglion lesions: the vagus nerves in FAP showed very extensive endoneurial deposition of amyloid with severe loss of myelinated nerve fibers, but in AL-amyloidosis there was no loss of myelinated nerve fibers and only slight amyloid deposition in the endoneurium. Similarly, in the celiac ganglion, intraganglionic deposition of amyloid was prominent in FAP and slight in AL-amyloidosis. It is known that bowel symptoms frequently occur in type I FAP and are less prominent in AL-amyloidosis. This study demonstrated that the gastrointestinal autonomic nerves were more markedly disturbed by amyloid in the former than in the latter, and disorder in neural control of the digestive tact may be responsible for the bowel symptoms in systemic amyloidosis, especially in type I FAP.

喉頭気管気管支アミロイドーシスの１症例

A case of amyloidosis localized in the laryngo-tracheo-bronchial area is reported. The patient was a 30-year-old man who complained of persistent hoarseness of 5 years duration and dyspnea of 3 months duration.Tracheostomy and subsequent direct laryngoscopy and bronchofiberscopy were done.These examinations revealed a marked, submucosal thickening of the bilateral false cord, and tracheo-bronchial stenosis with yellowish tumor forming nodules.Histological examination showed diffuse deposits of homogenous eosinophilic substances.A polarized microscopic examination with congo-red stain indicated that the material were amyloid.Because of the extensive deposition of amyloid, surgical resection was impossible. After tracheostomy, his respiratory function was improved.