Presence Of Amyloid Deposits Research Articles

A targeted proteomics approach to amyloidosis typing

BackgroundAmyloidosis is a life threatening disease caused by deposition of various types of blood serum proteins in organs and tissues. Knowing the type of protein involved is the basis of a correct diagnosis and personalized medical treatment. While the classical approach uses immunohistochemistry, in recent years, laser micro-dissection, followed by high resolution LC-MS/MS, has been shown to provide superior diagnostic sensitivity and specificity. This techniques, however, is only available at major reference proteomics centers. ObjectiveTo perform clinical amyloid protein typing using low-resolution mass spectrometry and no laser micro dissection (LMD), we developed a targeted proteomics approach for the determination of both frequently encountered amyloid proteins (i.e., κ and -λ immunoglobulin light chains and transthyretin (TTR)) and specific reference proteins (i.e., actin (A) for cardiac muscle tissue, or fatty acid binding protein 4 (FBP4) for subcutaneous adipose tissue) in histologic specimens. MethodSmall tissue fragments and/or histological sections were digested to yield a protein mixture that was subsequently reduced, alkylated and trypsinized to obtain a peptide mixture. After SPE purification and LC separation, proteotypic peptides were detected by their MRM transitions. ResultsThe method showed high specificity and sensitivity for amyloid protein proteotypic peptides. LODs were 1.0, 0.1, 0.2 picomoles in cardiac muscle tissue (CMT) and 0.1, 0.2, 0.5 picomoles in subcutaneous adipose tissue (SAT) for TTR, κ-, and λ-LC proteins, respectively. Amyloid to tissue-specific protein signal ratios correlated with the presence of amyloid deposits in clinical samples. ConclusionsThis targeted proteomics approach enables sensitive and specific discrimination of amyloidosis affected tissues for the purpose of clinical research.

Histopathology, microbiology and the inflammatory process associated with Sarcoptes scabiei infection in the Iberian ibex, Capra pyrenaica

BackgroundSarcoptic mange has been identified as the most significant infectious disease affecting the Iberian ibex (Capra pyrenaica). Despite several studies on the effects of mange on ibex, the pathological and clinical picture derived from sarcoptic mange infestation is still poorly understood. To further knowledge of sarcoptic mange pathology, samples from ibex were evaluated from histological, microbiological and serological perspectives.MethodsSamples of skin, non-dermal tissues and blood were collected from 54 ibex (25 experimentally infected, 15 naturally infected and 14 healthy). Skin biopsies were examined at different stages of the disease for quantitative cellular, structural and vascular changes. Sixteen different non-dermal tissues of each ibex were taken for histological study. Acetylcholinesterase and serum amyloid A protein levels were evaluated from blood samples from ibex with different lesional grade. Samples of mangy skin, suppurative lesions and internal organs were characterized microbiologically by culture. Bacterial colonies were identified by a desorption/ionization time-of-flight mass spectrometry system (MALDI TOF/TOF).ResultsThe histological study of the skin lesions revealed serious acanthosis, hyperkeratosis, rete ridges, spongiotic oedema, serocellular and eosinophilic crusts, exocytosis foci, apoptotic cells and sebaceous gland hyperplasia. The cellular response in the dermis was consistent with type I and type IV hypersensitivity responses. The most prominent histological findings in non-dermal tissues were lymphoid hyperplasia, leukocytosis, congestion and the presence of amyloid deposits. The increase in serum concentrations of acetylcholinesterase and amyloid A protein correlated positively with the establishment of the inflammatory response in mangy skin and the presence of systemic amyloidosis. A wide variety of bacterial agents were isolated and the simultaneous presence of these in mangy skin, lymph nodes and internal organs such as lungs, liver, spleen and kidney was compatible with a septicaemic pattern of infection.ConclusionsThe alteration of biomarkers of inflammation and its implication in the pathogenesis of the disease and development of lesions in non-dermal tissues and septicaemic processes are serious conditioners for the survival of the mangy ibex. This severe clinical picture could be an important factor when considering the decision to eliminate animals that exceed a certain disease threshold from a population.

Structural abnormalities in islets from very young children with cystic fibrosis may contribute to cystic fibrosis-related diabetes

Cystic fibrosis (CF)-related diabetes (CFRD) is thought to result from beta-cell injury due in part to pancreas exocrine damage and lipofibrosis. CFRD pancreata exhibit reduced islet density and altered cellular composition. To investigate a possible etiology, we tested the hypothesis that such changes are present in CF pancreata before the development of lipofibrosis. We evaluated pancreas and islet morphology in tissues from very young CF children (<4 years of age), and adult patients with CF and CFRD. The relative number of beta-cells in young CF tissues was reduced by 50% or more when compared to age-matched controls. Furthermore, young CF tissues displayed significantly smaller insulin-positive areas, lower proportion of beta-cells positive for the proliferation marker Ki67 or the ductal marker CK19 vs. control subjects, and islet inflammatory cell infiltrates, independently of the severity of the exocrine lesion and in the absence of amyloid deposits. CFRD pancreata exhibited greater islet injury with further reduction in islet density, decreased relative beta-cell number, and presence of amyloid deposits. Together, these results strongly suggest that an early deficiency in beta-cell number in infants with CF may contribute to the development of glucose intolerance in the CF pediatric population, and to CFRD, later in life.

The human serum protein C4b-binding protein inhibits pancreatic IAPP-induced inflammasome activation

Aims/hypothesisInflammasome activation and subsequent IL-1β production is a driver of islet pathology in type 2 diabetes. Oligomers, but not mature amyloid fibrils, of human islet amyloid polypeptide (IAPP), which is co-secreted with insulin, trigger NOD-like receptor pyrin domain containing-3 (NLRP3) inflammasome activation. C4b-binding protein (C4BP), present in serum, binds to IAPP and affects transition of IAPP monomers and oligomers to amyloid fibrils. We therefore hypothesised that C4BP inhibits IAPP-mediated inflammasome activation and IL-1β production.MethodsMacrophages were exposed to IAPP in the presence or absence of plasma-purified human C4BP, and inflammasome activation was assessed by IL-1β secretion as detected by ELISA and reporter cell lines. IAPP fibrillation was assessed by thioflavin T assay. Uptake of IAPP–C4BP complexes and their effects on phagolysosomal stability were assessed by flow cytometry and confocal microscopy. The effect of C4BP regulation of IAPP-mediated inflammasome activation on beta cell function was assessed using a clonal rat beta cell line. Immunohistochemistry was used to examine the association of IAPP amyloid deposits and macrophage infiltration in isolated human and mouse pancreatic islets, and expression of C4BP from isolated human pancreatic islets was assessed by quantitative PCR, immunohistochemistry and western blot.ResultsC4BP significantly inhibited IAPP-mediated IL-1β secretion from primed macrophages at physiological concentrations in a dose-dependent manner. C4BP bound to and was internalised together with IAPP. C4BP did not affect IAPP uptake into phagolysosomal compartments, although it did inhibit its formation into amyloid fibrils. The loss of macrophage phagolysosomal integrity induced by IAPP incubation was inhibited by co-incubation with C4BP. Supernatant fractions from macrophages activated with IAPP inhibited both insulin secretion and viability of clonal beta cells in an IL-1β-dependent manner but the presence of C4BP during macrophage IAPP incubation rescued beta cell function and viability. In human and mouse islets, the presence of amyloid deposits correlated with higher numbers of infiltrating macrophages. Isolated human islets expressed and secreted C4BP, which increased with addition of IL-1β.Conclusions/interpretationIAPP deposition is associated with inflammatory cell infiltrates in pancreatic islets. C4BP blocks IAPP-induced inflammasome activation by preventing the loss of macrophage phagolysosomal integrity required for NLRP3 activation. The consequence of this is the preservation of beta cell function and viability. C4BP is secreted directly from human pancreatic islets and this increases in response to inflammatory cytokines. We therefore propose that C4BP acts as an extracellular chaperone protein that limits the proinflammatory effects of IAPP.

THERAPEUTIC APPROACH OF A CASE OF RHEUMATOID ARTHRITIS COMPLICATED WITH RENAL AMYLOIDOSIS IN A YOUNG WOMAN

Systemic AA amyloidosis is an uncommon complication of rheumatoid arthritis (RA), especially in poorly controlled RA. Renal involvement caused by deposits of amyloid fibrils derived from acute-phase proteins is represented by nephrotic-range proteinuria ultimately leading to renal failure. We report the case of 27-year-old woman diagnosed with RA, with a history of musculoskeletal involvement since the age of 16, manifested by arthritis involving the wrists, knees and ankles; accompanied by severe and persistent inflammatory syndrome. She presented with an active form of RA complicated with secondary amyloidosis manifested by nephrotic-range proteinuria at the time of admission. Renal biopsy confirmed the presence of amyloid deposits. Anti-TNFα therapy with Certolizumab pegol proved effective in reducing proteinuria and inflammatory biomarker levels in our patient. The efficacy of anti TNF-α therapy in RA complicated with renal amyloidosis is demonstrated by recent scientific data.

The cingulate cortex of older adults with excellent memory capacity

Memory deterioration is the earliest and most devastating cognitive deficit in normal aging and Alzheimer's disease (AD). Some older adults, known as “Supernormals”, maintain excellent memory. This study examined relationships between cerebral amyloid deposition and functional connectivity (FC) within the cingulate cortex (CC) and between CC and other regions involved in memory maintenance between Supernormals, healthy controls (HC), and those at risk for AD (amnestic mild cognitive impairment [MCI]). Supernormals had significantly stronger FC between anterior CC and R-hippocampus, middle CC (MCC) and L-superior temporal gyrus, and posterior CC (PCC) and R-precuneus, while weaker FC between MCC and R-middle frontal gyrus and MCC and R-thalamus than other groups. All of these FC were significantly related to memory and global cognition in all participants. Supernormals had less amyloid deposition than other groups. Relationships between global cognition and FC were stronger among amyloid positive participants. Relationships between memory and FC remained regardless of amyloid level. This revealed how CC-related neural function participates in cognitive maintenance in the presence of amyloid deposition, potentially explaining excellent cognitive function among Supernormals.

ALZHEIMER’S DISEASE: DELIVERY OF DRUGs THROUGH INTRANASAL ROUTE

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by severe cognitive impairments. A major histopathological hallmark of AD is the presence of amyloid deposits in the parenchyma of the amygdala, hippocampus, and neocortex. I²-amyloid is a small piece of a larger protein called “amyloid precursor protein” (APP). The main component of amyloid is the I²-Amyloid protein (AI²), a 39.43 amino acid peptide composed of a portion of the transmembrane domain and the extracellular domain of the APP. AI² deposition leads to synaptic degeneration and interacts with different types of central nervous system receptors; hence, it disrupts neuronal homeostasis. Moreover, AI² deposition along the cerebral vessels alters their tonicity and triggers some of the cerebrovascular deficits. Furthermore, its accumulation disrupts intracellular Ca2+ homeostasis which ultimately reduces neuronal Ca2+ buffering capacity and increases excitotoxicity outcomes. The emerging approach is to bypass the BBB by intranasal delivery, which provides a practical, noninvasive, rapid and simple method to deliver the therapeutic agents to the CNS. This method works the unique connection between the nose and the brain that has evolved to sense odors and other chemical stimuli. On the basis of clinical trials (Phase I and II) it is reported that the intranasal route is feasible for the transport of the drug to the CNS. Intranasal delivery does not require any modification of the therapeutic agents and does not require that drugs be coupled with any carrier like in case of drug delivery across the BBB. A wide variety of therapeutic agents, including both small molecules and macromolecules can be successfully delivered, including to the CNS, using the intranasal method.  Key Words: Alzheimer’s disease, I²-amyloid, cerebrovascular deficits, excitotoxicity

Why are prions and amyloid structures immune suppressive and other intriguing questions facing neuroimmunologists in the future

The immune system plays a major role in certain diseases of the brain like multiple sclerosis and neuromyelitis optica, while the brain may play a major role in modulating certain immunologic diseases of the periphery like inflammatory bowel disease. The most significant developments in neuroimmunology will involve explorations of the roles for the immune system in neurodegenerative conditions often associated with the presence of amyloid deposits. Here I present my personal perspectives on four of the most intriguing challenges that we face in the future of neuroimmunology: (1) Why are the traditional hallmarks of innate and adaptive inflammation conspicuously absent from brains of individuals with prion disease and amyloid pathology? (2) What is the role of adaptive and innate immunity in progressive forms of multiple sclerosis? (3) Is molecular mimicry an adequate explanation for the initiation of neuroinflammatory disease and for exacerbations in conditions like multiple sclerosis, narcolepsy, and neuromyelitis optica? (4) Do neural pathways regulate inflammatory diseases outside the nervous system?

Systemic AL-amyloidosis

A 62-year-old man came to our outpatient clinic with purpura on his eyelids. 7 months before, periocular purpura appeared after a minimal trauma. These lesions did not resolve for months. He also reported fatigue over the previous 6 months. On examination pinch purpura between smooth waxy papules were found (fi gure). Histological examination showed accumulation of amorphous eosinophilic masses below the epidermis in the papillary and upper reticular dermis, around sweat glands and hair follicles. Staining for thio fl avine T showed yellow-green immuno fl uores cence (fi gure). Congo red staining showed apple-green bire fringence on polarised light microscopy, indi cating amyloid deposits. Serum protein electrophoresis showed the presence of a monoclonal (M) protein. Immunofi xation of both serum and urine determined its type: IgA-λ-type Bence-Jones protein. Bone-marrow examin ation was diagnostic for myeloma. Radiography showed small osteolysis of the head and cervical spine. Further investigations showed bilateral carpal tunnel syndrome and cardiac involvement. The diagnosis of systemic ALamyloidosis was made from the com bination of clinical fi ndings, the presence of amyloid deposits in skin biopsy sample, and the plasma cell dyscrasia. Treatment with bortezomib, cyclophos phamide, and dexamethasone was given. Autologous haemopoietic cell trans plan tation is planned. Systemic AL-amyloidosis is a rare and severe disease. Bruising purpura around the eyelids combined with yellow waxy papules are typical clinical signs suspicious for systemic AL-amyloidosis. This disease occurs in patients with plasma cell dyscrasia, in particular multiple myeloma. Amyloid is composed of a fi brillar component (immunoglobulin light chain material derived from the abnormal paraprotein) and a nonfi brillar protein termed amyloid P component. It deposits in extracellular tissue of several organs (skin, kidney, heart, liver, and peripheral nerve system). The prognosis depends on the number and severity of internal organ involvement and haematological response to treatment.

Tau–amyloid interactions in the rTgTauEC model of early Alzheimer's disease suggest amyloid‐induced disruption of axonal projections and exacerbated axonal pathology

Early observations of the patterns of neurofibrillary tangles and amyloid plaques in Alzheimer's disease suggested a hierarchical vulnerability of neurons for tangles, and a widespread nonspecific pattern of plaques that nonetheless seemed to correlate with the terminal zone of tangle-bearing neurons in some instances. The first neurofibrillary cortical lesions in Alzheimer's disease occur in the entorhinal cortex, thereby disrupting the origin of the perforant pathway projection to the hippocampus, and amyloid deposits are often found in the molecular layer of the dentate gyrus, which is the terminal zone of the entorhinal cortex. We modeled these anatomical changes in a transgenic mouse model that overexpresses both P301L tau (uniquely in the medial entorhinal cortex) and mutant APP/PS1 (in a widespread distribution) to examine the anatomical consequences of early tangles, plaques, or the combination. We find that tau uniformly occupies the terminal zone of the perforant pathway in tau-expressing mice. By contrast, the addition of amyloid deposits in this area leads to disruption of the perforant pathway terminal zone and apparent aberrant distribution of tau-containing axons. Moreover, human P301L tau-containing axons appear to increase the extent of dystrophic axons around plaques. Thus, the presence of amyloid deposits in the axonal terminal zone of pathological tau-containing neurons profoundly impacts their normal connectivity.

Influencia de la inflamación y la presencia de amiloide sobre el metabolismo lipídico en pacientes con artritis reumatoide

IntroductionPatients with rheumatoid arthritis (RA) display an accelerated atherosclerosis that is related in part to lipid metabolism disorders associated with the inflammatory process, which includes serum amyloid protein A. ObjectiveTo evaluate the lipid profile in treated RA patients and its relationship to inflammatory activity and the presence of secondary amyloidosis. MethodsSeventy-eight female patients with RA were studied. Blood samples were obtained from all patients, to analyze the lipid profile (total cholesterol, HDL-c, HDL3-c, HDL2-c, LDL-c, triglycerides, lipoprotein(a) and apolipoproteinsAI and B), an abdominal fat pad aspirate was performed to determinate the presence of amyloid, and the activity of the disease by clinical and laboratory parameters was evaluated. The control group was selected from a population-based study. ResultsThe RA patients had significantly higher concentrations of HDL-c and lower of apolipoprotein B than selected general population. Amyloid deposition was detected in 11%, and compared to patients without amyloidosis, significant differences in HDL-c concentrations was not observed, although the HDL3-c was higher, with differences near to statistical significance (p=0.087). Inflammatory activity correlated negatively with HDL-c, HDL3-c and apolipoprotein AI in RA patients. ConclusionsThere is a significant negative correlation between cardioprotective lipid parameters and inflammatory activity in women with treated RA, that is not related with the presence of amyloid deposits.

Distribution and binding of 18F-labeled and 125I-labeled analogues of ACI-80, a prospective molecular imaging biomarker of disease: A whole hemisphere post mortem autoradiography study in human brains obtained from Alzheimer’s disease patients

One of the major pathological landmarks of Alzheimer’s disease and other neurodegenerative diseases is the presence of amyloid deposits in the brain. The early non-invasive visualization of amyloid is a major objective of recent diagnostic neuroimaging approaches, including positron emission tomography (PET), with an eye on follow-up of disease progression and/or therapy efficacy. The development of molecular imaging biomarkers with binding affinity to amyloid in the brain is therefore in the forefront of imaging biomarker and radiochemistry research. Recently, a dodecamer peptide (amino acid sequence=QSHYRHISPAQV; denominated D1 or ACI-80) was identified as a prospective ligand candidate, binding with high ex vivo affinity to L-Aβ-amyloid (Kd: 0.4μM). In order to assess the ligand’s capacity to visualize amyloid in Alzheimer’s disease (AD), two 125I labeled and three 18F labeled analogues of the peptide were synthesized and tested in post mortem human autoradiography experiments using whole hemisphere brain slices obtained from deceased AD patients and age matched control subjects. The 18F-labeled radioligands showed more promising visualization capacity of amyloid that the 125I-labeled radioligands. In the case of each 18F radioligands the grey matter uptake in the AD brains was significantly higher than that in control brains. Furthermore, the grey matter: white matter uptake ratio was over ∼2, the difference being significant for each 18F-radioligands. The regional distribution of the uptake of the various radioligands systematically shows a congruent pattern between the high uptake regions and spots in the autoradiographic images and the disease specific signals obtained in adjacent or identical brain slices labeled with histological, immunohistochemical or autoradiographic stains for amyloid deposits or activated astrocytes. The present data, using post mortem human brain autoradiography in whole hemisphere human brains obtained from deceased AD patients and age matched control subjects, support the visualization capacity of the radiolabeled ACI-80 analogues of amyloid deposits in the human brain. Further studies are warranted to explore the usefulness of the 18F-labeled analogues as in vivo molecular imaging biomarkers in diagnostic PET studies.

SAP suppresses the development of experimental autoimmune encephalomyelitis in C57BL/6 mice

Experimental autoimmune encephalomyelitis (EAE) is a CD4(+) T cell-mediated disease of the central nervous system. Serum amyloid P component (SAP) is a highly conserved plasma protein named for its universal presence in amyloid deposits. Here we report that SAP-transgenic mice had unexpectedly attenuated EAE due to impaired encephalitogenic responses. Following induction with myelin oligodendroglial glycoprotein (MOG) peptide 35-55 in complete Freund's adjuvant, SAP-transgenic mice showed reduced spinal cord inflammation with lower severity of EAE attacks as compared with control C57BL/6 mice. However, in SAP-Knockout mice, the severity of EAE is enhanced. Adoptive transfer of Ag-restimulated T cells from wild type to SAP-transgenic mice, or transfer of SAP-transgenic Ag-restimulated T cells to control mice, induced milder EAE. T cells from MOG-primed SAP-transgenic mice showed weak proliferative responses. Furthermore, in SAP-transgenic mice, there is little infiltration of CD45-positive cells in the spinal cord. In vitro, SAP suppressed the secretion of interleukin-2 stimulated by P-selectin and blocked P-selectin binding to T cells. Moreover, SAP could change the affinity between α4-integrin and T cells. These data suggested that SAP could antagonize the development of the acute phase of inflammation accompanying EAE by modulating the function of P-selectin.

AL Amyloidosis: Prognosis of Cardiac Involvement Reconsidered.

Abstract 4872 BackgroudPrognosis in AL amyloidosis is commonly viewed as dichotomous, based on the presence or absence of cardiac involvement. Patients with cardiac AL amyloidosis are reported to have a dismal prognosis, with a median survival of approximately 6 months. Furthermore, cardiac involvement is often considered a contraindication to hematopoietic cell transplant. AimsTo compare the prognosis of patients with cardiac AL amyloidosis with and without presenting symptoms of congestive heart failure (CHF). MethodsThe study population consisted of individuals with biopsy-proven AL amyloidosis and cardiac involvement seen at the Stanford University Amyloid Center. Cardiac involvement was defined by the presence of amyloid deposits on endomyocardial biopsy or the combination of increased ventricular mass with reduced electrocardiographic voltage. ResultsA total of 27 patients (median age 64 years, 37% female) were evaluated. The 16 patients with CHF symptoms had a median age of 65 years with a median of 2 organs involved with amyloidosis. The 11 patients without CHF symptoms had a median age of 59 years with a median of 3 organs involved. At diagnosis, NT-proBNP was significantly higher in the group with CHF symptoms (15,938 vs. 2,538 pg/ml, P<0.001), as was the likelihood of detectable troponin I (86% s. 36%, P<0.02). Mean levels of the involved serum free light chain (179.7 vs. 47.9 mg/dL) were nonsignificantly higher in the cohort with CHF. Though there was no difference in the mean interventricular septal width between the two groups (1.5 cm), the mean systolic blood pressure (sBP) (91 vs. 115 mm Hg, P<0.001) and left ventricular ejection fraction (45 vs. 59%, p=0.02) were significantly lower in the group with CHF symptoms. A total of 6 patients (4 without CHF symptoms, 2 with CHF symptoms) received hematopoietic cell transplants, and 3 patients received heart transplants. Other therapies employed included oral melphalan (6 patients), dexamethasone (19 patients), lenalidomide (17 patients), and bortezomib (4 patients). After a median follow-up of 24 months, there were 9 deaths in the cohort with CHF symptoms vs. 0 in the group without CHF symptoms. Six-month survival (50% vs. 100%, P<0.01) and one-year survival (42% vs. 100%, P<0.01) were significantly lower in the group with CHF symptoms. DiscussionCHF at presentation is the primary factor which predicts a poor prognosis in patients with cardiac AL amyloidosis. In our cohort, no patient without CHF symptoms at diagnosis later developed CHF, and thus new CHF symptoms do not appear to be a typical consequence of progressive disease. ConclusionNot all patients with cardiac AL amylodosis have an exceptionally poor prognosis. Many patients have ‘incidental' cardiac involvement in the absence of CHF symptoms and appear to do well with both standard and intensive therapies. DisclosuresWitteles:Celgene: Research Funding. Off Label Use: Melphalan, lenalidomide & bortezomib as therapy for AL amyloidosis.. Witteles:Celgene: Research Funding. Schrier:Celgene: Research Funding.

A New Tacrine–Melatonin Hybrid Reduces Amyloid Burden and Behavioral Deficits in a Mouse Model of Alzheimer’s Disease

Alzheimer's disease (AD) is a progressive degenerative disorder characterized by the presence of amyloid deposits, neurofibrillary tangles and neuron loss. Emerging evidence indicates that antioxidants could be useful either for the prevention or treatment of AD. Tacrine and melatonin are well-known drugs which act as an acetylcholinesterase inhibitor and a free radical scavenger, respectively. In this study, we evaluated the effects of a new tacrine-melatonin hybrid on behavior and the biochemical and neuropathologic changes observed in amyloid precursor protein/presenilin 1 (APP/Ps1) transgenic mice. Our findings showed that direct intracerebral administration of this hybrid decreased amyloid beta peptide (Abeta)-induced cell death and amyloid burden in the brain parenchyma of APP/Ps1 mice. This reduction in Abeta pathology was accompanied by a recovery in cognitive function. Since this tacrine-melatonin hybrid apparently reduces brain Abeta and behavioral deficits, we believe this drug has remarkable and significant neuroprotective effects and might be considered a potential therapeutic strategy in AD.

Amiloidosis cutánea localizada secundaria a poroqueratosis. Estudio histopatológico retrospectivo de 30 pacientes

IntroductionPorokeratosis is a rare disorder of keratinization. The presence of amyloid deposits has been observed in inflammatory and tumoral skin diseases. ObjectivesThe aim of this study was to determine the frequency of cutaneous amyloidosis in histology samples from various types of porokeratosis diagnosed in our department from 1988 to 2005. Material and methodsThirty patients were selected and 34 biopsies of lesions clinically and histologically compatible with porokeratosis were performed. Sections were stained with hematoxylin-eosin and thioflavin T. ResultsAmyloid deposits were observed in 11 biopsies from 9 patients. Most were women in their sixties, with disseminated superficial actinic porokeratosis that had begun at least 5 years earlier. No notable histologic differences were observed between porokeratosis specimens with and without amyloid deposits. ConclusionsThe coexistence of porokeratosis and amyloidosis is a rare occurrence but may be underdiagnosed. In our opinion, the advanced age of the patients and the chronic nature of the lesions would have been predisposing factors for amyloid deposition. The possibility of racial or genetic influences, however, cannot be ruled out.

Primary central nervous system vasculitis: comparison of patients with and without cerebral amyloid angiopathy

To describe the clinical features and outcomes of patients with primary central nervous system vasculitis (PCNSV) and cerebral amyloid angiopathy (CAA) from a large cohort of consecutive patients with PCNSV treated at a single institution. We identified 101 consecutive patients with PCNSV admitted between January 1983 and December 2003. PCNSV diagnoses were based on findings from a central nervous system (CNS) biopsy (n = 31) and conventional angiography (n = 70). CNS tissue specimens from 49 cases were examined histologically, and 49 were stained for amyloid deposits. Those with vascular amyloid deposits (CAA) were compared with those without histological evidence of amyloid deposition. Eight cases (26%) with CNS biopsy specimens positive for PCNSV also showed findings of CAA. Compared with patients with PCNSV only, these patients were older at diagnosis, predominantly male, had a more acute onset, a higher frequency of cognitive dysfunction and showed prominent gadolinium-enhanced leptomeningeal lesions with MRI. Histologically, all had a granulomatous vascular inflammatory pattern. Six patients responded promptly to therapy. Outcomes at last follow-up were similar in the two groups. PCNSV with CAA appears to form a clinical subset of PCNSV. The vasculitis influences the clinical findings to a greater degree than the presence of amyloid deposits in the vessels.

Localized Cutaneous Amyloidosis Secondary to Porokeratosis: A Retrospective Histopathologic Study of 30 Patients

Introduction Porokeratosis is a rare disorder of keratinization. The presence of amyloid deposits has been observed in inflammatory and tumoral skin diseases. Objectives The aim of this study was to determine the frequency of cutaneous amyloidosis in histology samples from various types of porokeratosis diagnosed in our department from 1988 to 2005. Material and methods Thirty patients were selected and 34 biopsies of lesions clinically and histologically compatible with porokeratosis were performed. Sections were stained with hematoxylin-eosin and thioflavin T. Results Amyloid deposits were observed in 11 biopsies from 9 patients. Most were women in their sixties, with disseminated superficial actinic porokeratosis that had begun at least 5 years earlier. No notable histologic differences were observed between porokeratosis specimens with and without amyloid deposits. Conclusions The coexistence of porokeratosis and amyloidosis is a rare occurrence but may be underdiagnosed. In our opinion, the advanced age of the patients and the chronic nature of the lesions would have been predisposing factors for amyloid deposition. The possibility of racial or genetic influences, however, cannot be ruled out.

Quantitative MRI reveals aging‐associated T2 changes in mouse models of Alzheimer's disease

In this study, we used MRI to analyze quantitative parametric maps of transverse (T(2)) relaxation times in a longitudinal study of transgenic mice expressing mutant forms of amyloid precursor protein (APP), presenilin (PS1), or both (PS/APP), modeling aspects of Alzheimer's disease (AD). The main goal was to characterize the effects of progressive beta-amyloid accumulation and deposition on the biophysical environment of water and to investigate if these measurements would provide early indirect evidence of AD pathological changes in the brains of these mice. Our results demonstrate that at an early age before beta-amyloid deposition, only PS/APP mice show a reduced T(2) in the hippocampus and cortex compared with wild-type non-transgenic (NTg) controls, whereas a statistically significant within-group aging-associated decrease in T(2) values is seen in the cortex and hippocampus of all three transgenic genotypes (APP, PS/APP, and PS) but not in the NTg controls. In addition, for animals older than 12 months, we confirmed our previous report that only the two genotypes that form amyloid plaques (APP and PS/APP) have significantly reduced T(2) values compared with NTg controls. Thus, T(2) changes in these AD models can precede amyloid deposition or even occur in AD models that do not deposit beta-amyloid (PS mice), but are intensified in the presence of amyloid deposition.

Primary Localized Orbital Amyloidosis: A Case Report

Amyloidosis refers to a heterogeneous group of disorders associated with deposition of chemically distinct fibril proteins. Isolated orbital amyloidosis is a rare condition and requires systemic examination. The authors report a case of amyloid deposit in the orbit whose systemic investigation has been negative. A 64-year-old woman presented to the eye clinic with left-sided orbital mass, mild exophthalmos with downward ocular displacement, and ptosis. The patient presented also visual acuity loss and ocular hypertension. No systemic involvement was noted by systemic workup and it confirmed the primary orbital amyloidosis. The patient was subject to full clinical examination, laboratory examinations, orbital echography, magnetic resonance imaging and total body computed tomography scans, rectal mucosa, and temporal artery biopsies. It was necessary to exclude systemic amyloidosis. The presence of amyloid deposits was confirmed by biopsy of orbital mass. The chemical nature of deposit was characterized using light microscopy, immunohistochemistry, and electron microscopy. Orbital amyloidosis is a very rare disease. It should be considered in the diagnosis of patients with ptosis and exophthalmos. The treatment usually consists of surgical removal of the amyloid mass and follow-up for a likely local recurrence. In our case, mass excision determined the decrease of exophthalmos and intraocular pressure.