Showing papers in "Amyloid in 2014"
TL;DR: The Nomenclature Committee of the International Society of Amyloidosis met during the XIVth Symposium of the Society, April 27–May 1, 2014, Indianapolis, IN, to assess and formulate recommend new names for amyloid beta-cell types.
Abstract: The Nomenclature Committee of the International Society of Amyloidosis (ISA) met during the XIVth Symposium of the Society, April 27–May 1, 2014, Indianapolis, IN, to assess and formulate recommend...
433 citations
TL;DR: Bone scintigraphy with 99mTc-HDP may detect cardiac involvement in patients with ATTR amyloidosis prior to echocardiographic evidence of cardiac involvement.
Abstract: Objective: To assess the usefulness of bone scintigraphy with 99mTechnetium-hydroxymethylene diphosphonate (99mTc-HDP) for the detection of cardiac involvement in a group of patients with ATTR amyloidosis in different phases of disease, to relate the findings to echocardiography, ECG and cardiac biomarkers, and to evaluate different bone scintigraphic techniques and calculation methods for quantification of the cardiac uptake and for correlation with echocardiographic features and cardiac biomarkers.Methods: Forty-one patients underwent clinical examinations, echocardiography, ECG, measurement of cardiac biomarkers and bone scintigraphy (planar imaging and SPECT-CT) and were subsequently subdivided into three groups: (1) carriers of an amyloidogenic TTR mutation, n = 11, (2) proven ATTR amyloidosis without echocardiographically-defined (mean wall thickness >12 mm) cardiac amyloidosis (AC), n = 19, and (3) ATTR amyloidosis with echocardiographically-defined cardiac amyloidosis, n = 11. Planar and S...
126 citations
TL;DR: Gain of 1q21 was identified as an independent adverse prognostic factor in AL amyloidosis patients treated with standard chemotherapy and deletion 13q14 and hyperdiploidy turned out to be prognostically neutral.
Abstract: Chromosomal aberrations of plasma cells are well established pathogenetic and prognostic factors in multiple myeloma, but their prognostic implication in systemic light chain (AL) amyloidosis is un...
78 citations
TL;DR: In Japanese type 2 diabetic patients, islet amyloid was more common with severe β-cell loss and high BMI, associated with macrophage infiltration, and correlated with reduced volume densities of β- cell and α-cell, but not with duration of diabetes, age or HbA1c.
Abstract: Aims: Islet amyloid is a hallmark in type 2 diabetic subjects, but its implication in clinical features and development of islet pathology is still unclear.Methods: From 118 autopsy cases with type 2 diabetes, 26 cases with islet amyloid deposition (DA+) were selected. Twenty diabetic subjects without obvious amyloid deposition (DA−) matched for the age and diabetes duration and 20 non-diabetic subjects (ND) served for comparison. We examined the severity of amyloid deposition and its relationships with population of endocrine cells, expression of cell damage markers or macrophage infiltration. Correlation of clinical profile with islet pathology was also sought on the subset of the investigated patients.Results: β-Cell volume density was nearly 40% less in DA+ and 20% less in DA− when compared to ND. Severity of amyloid deposition correlated with reduced volume densities of β-cell and α-cell, and increased body mass index (BMI), but not with duration of diabetes, age or HbA1c. Amyloid-rich islets...
73 citations
TL;DR: The amyloid proteome is analyzed in 52 cases of insulin and enfuvirtide associated amyloidsosis using laser microdissection/tandem mass spectrometry and it is shown that the deposits are composed of the drug, as well as otherAmyloid precursor proteins such as apolipoproteins A-I, A-IV, E and serum isyloid protein.
Abstract: Protein and peptide drugs administered subcutaneously, such as insulin can be amyloidogenic and result in localized amyloid deposits at the sites of medication injections. These iatrogenic amyloidoses typically present as a localized subcutaneous nodule or skin reaction at the site of administration, and often pose diagnostic challenges. We have analyzed the amyloid proteome in 52 cases of insulin and enfuvirtide associated amyloidosis using laser microdissection/tandem mass spectrometry. We show that the deposits are composed of the drug, as well as other amyloid precursor proteins such as apolipoproteins A-I, A-IV, E and serum amyloid protein. Mass spectrometry-based amyloid sub-typing allows for accurate amyloid diagnosis with resultant therapeutic and prognostic implications. This insight into the amyloid proteome in drug-induced amyloidosis may help further understand pathogenesis of amyloid fibril formation.
68 citations
TL;DR: A novel gelsolin variant is reported in a 62-year-old man with nephrotic range proteinuria of 13.2 grams/day as the only presenting symptom and one who proceeded to renal biopsy and was confirmed to have renal amyloidosis.
Abstract: Familial Amyloidosis of Finnish type (FAF) is a rare type of autosomal dominant hereditary amyloidosis associated with genetic variants of gelsolin. Three amyloidogenic mutations have previously been reported characteristically presenting with ophthalmologic abnormalities, progressive cranial neuropathy and cutis laxa. We report a novel gelsolin variant in a 62 year old man with nephrotic range proteinuria of 13.2 grams/day as the only presenting symptom. Renal biopsy followed by laser microdissection and mass spectrometry showed amyloidosis derived from gelsolin. DNA sequencing revealed the novel gelsolin mutation (c.633C>A) encoding p.N211K protein variant. Four of 13 asymptomatic family members were found to be heterozygous for the p.N211K mutation, three of whom had proteinuria of varying degree including one who proceeded to renal biopsy and was confirmed to have renal amyloidosis. Follow up of these cases might give us more insight into pathogenicity and potential treatment strategy of this atypical presentation of gelsolin amyloidosis.
37 citations
TL;DR: Treatment with Anakinra prevents transthyretin extracellular deposition in sciatic nerve, protecting unmyelinated nerve fibers from aggregate-induced degeneration and highlights the relevance of the IL-1 signaling pathway in the pathophysiology of FAP.
Abstract: Introduction: Inflammation is a key pathological hallmark of several neurodegenerative disorders including Alzheimer’s disease, Parkinson’s disease and familial amyloidotic polyneuropathy (FAP). Among all inflammatory cytokines associated with FAP, IL-1b, in particular, has been implicated in playing a key pathogenic role. In the present study, we sought to investigate whether blocking IL-1b signaling provides disease-modifying benefits in an FAP mouse model. Methods: We assessed the effect of chronic administration of Anakinra, an IL-1 antagonist, on FAP pathogenesis in vivo, using real-time polymerase chain reaction (qPCR), semi-quantitative immunohistochemistry (SQ-IHC), western blot and nerve morphometric analyses. Results: We found that treatment with Anakinra prevents transthyretin (TTR) extracellular deposition in sciatic nerve, protecting unmyelinated nerve fibers from aggregate-induced degeneration. Moreover, Anakinra administration significantly suppressed IL-1 signaling pathway and inhibited apoptosis and nitrative stress. Conclusions: The present work highlights the relevance of the IL-1 signaling pathway in the pathophysiology of FAP. Our results bring to light the importance of non-amyloid targets in the therapeutic strategies for this disorder. Thus, we propose the use of Anakinra as a potential therapeutic agent for TTR-related amyloidosis. Abbreviations: BiP: binding immunoglobulin protein; DRG: dorsal root ganglia; ER: endoplasmic reticulum; FAP: familial amyloidotic polyneuropathy; Gapdh: glyceraldehyde 3-phosphate dehydrogenase; Hsf-1: heat shock factor 1; IL-1: interleukin-1; Hsp-27: heat shock protein-27; IL-1Ra: interleukin-1 receptor antagonist; Irak1: interleukin-1 receptor associated kinase-1; Myd88: myeloid differentiation primary response gene 88; NF-kB: nuclear factor kB; PBS: phosphate buffer saline; qPCR: real-time polymerase chain reaction; RAGE: receptor for advanced glycation end products; SEM: standard error of the mean; siRNA: small interfering RNA; mRNA: messenger RNA; SQ-IHC: semi-quantitative immunohistochemistry; TNF-a: tumor necrosis factor a; TTR: transthyretin; UPR: unfolded protein response; V30M: valine 30 methionine
35 citations
TL;DR: It is reported that a small molecule inhibitor prevents tau aggregation by blocking the generation of disulfide cross-linked tau oligomers in vitro and suggests that controlling tau oxidation status could be a new therapeutic strategy for prevention of abnormal t Tau aggregation.
Abstract: Abnormal tau aggregates are presumed to be neurotoxic and are an important therapeutic target for multiple neurodegenerative disorders including Alzheimer’s disease. Growing evidence has shown that tau intermolecular disulfide cross-linking is critical in generating tau oligomers that serve as a building block for higher-order aggregates. Here we report that a small molecule inhibitor prevents tau aggregation by blocking the generation of disulfide cross-linked tau oligomers. Among the compounds tested, a rosamine derivative bearing mild thiol reactivity selectively labeled tau and effectively inhibited oligomerization and fibrillization processes in vitro. Our data suggest that controlling tau oxidation status could be a new therapeutic strategy for prevention of abnormal tau aggregation.
32 citations
TL;DR: Cardiac involvement can be detected in patients with hereditary ATTR amyloidosis with isolated neurological symptoms and without left ventricular wall thickening, suggesting that CMR could be useful in detecting preclinical cardiac amyloidsosis.
Abstract: Background: Most of the studies that described cardiac amyloidosis using cardiac magnetic resonance (CMR) imaging refer to patients with primary light chain (AL) amyloidosis. The goal of this study was to evaluate cardiac involvement in patients with hereditary transthyretin associated (ATTR) amyloidosis and asymptomatic carriers and its relationships with clinical symptoms and genotype, using CMR imaging.Methods and results: Fifty-three patients with hereditary ATTR amyloidosis and 14 asymptomatic carriers were included in this study. Morphological, functional and late gadolinium enhancement (LGE) findings were noted on CMR images. A positive LGE suggesting cardiac amyloidosis was detected in 60% of patients. The pattern of LGE was diffuse, focal and circumferential in 32, 26 and 2% of patients, respectively. The inferior basal segment was the most frequently involved (93%) in case of focal involvement. Diffuse pattern was exclusively encountered in patients with cardiac symptoms. Nineteen percen...
30 citations
TL;DR: Though preliminary results suggest amyloid imaging to possess clinical utility and cost-effectiveness, both domains have yet to be assessed systematically and it is imperative that a broad range of stakeholders be involved to ensure the appropriateness of emerging policies and protocols.
Abstract: Recent advances have made possible the in vivo detection of beta-amyloid (Aβ) pathology using positron emission tomography. While the gold standard for amyloid imaging, carbon-11 labeled Pittsburgh compound B is increasingly being replaced by fluorine-18 labeled radiopharmaceuticals, with three already approved for clinical use by US and European regulatory bodies. Appropriate use criteria proposed by an amyloid imaging taskforce convened by the Alzheimer's Association and the Society of Nuclear Medicine and Molecular Imaging recommend restricting use of this technology to the evaluation of patients with mild cognitive impairment or atypical dementia syndromes. While use among asymptomatic individuals is currently viewed as inappropriate due prognostic uncertainty, elevated levels of brain Aβ among asymptomatic individuals may represent preclinical Alzheimer's disease. Amyloid imaging is likewise expected to play a role in the design of clinical trials. Though preliminary results suggest amyloid imaging to possess clinical utility and cost-effectiveness, both domains have yet to be assessed systematically. As the field moves toward adoption of a pro-disclosure stance for amyloid imaging findings, it is imperative that a broad range of stakeholders be involved to ensure the appropriateness of emerging policies and protocols.
29 citations
TL;DR: It is demonstrated that patients presenting with amyloid lymphadenopathy usually have AL amyloidsosis, and should have a thorough evaluation for other organ involvement at diagnosis, as well as be monitored regularly for development of other organ disease over time.
Abstract: Lymphadenopathy as a manifestation of amyloidosis is rare. Of 3008 new patients with amyloidosis evaluated from 1994 to 2013 at a single center, 47 (1.6%) presented with lymph node enlargement leading to a biopsy and the diagnosis. We conducted a retrospective review of the initial presentation, time to progression, and treatment outcomes for these patients. Upon initial evaluation, 14 (30%) had isolated lymphadenopathy while 33 (70%) had evidence of vital organ involvement. Thirty-nine patients (83%) had systemic AL amyloidosis at initial evaluation or developed it on follow up; there was a single case each of AA, wtTTR and V122ITTR and one untyped amyloidosis. Eleven patients (23%) had IgM monoclonal gammopathy and 3 (6%) had histology consistent with lymphoplasmacytic lymphoma. Of the 14 patients with isolated lymphadenopathy, 10 (71%) eventually progressed to other organ disease requiring treatment at a median time of 10 months (range 4-71). This series demonstrates that patients presenting with amyloid lymphadenopathy usually have AL amyloidosis, and should have a thorough evaluation for other organ involvement at diagnosis. If present, treatment should be similar to that of other patients with systemic AL amyloidosis, but if not, patients should be monitored regularly for development of other organ disease over time.
TL;DR: Genotyping a large number of samples from the Northern Sweden Health and Disease Study cohort found that a carrier frequency could be determined for the Skellefteå and Lycksele populations, but this does not change the previous finding of a surprisingly higher carrier frequency in the population from endemic area of Northern Sweden compared to that reported from endemic areas in Portugal.
Abstract: By genotyping a large number of samples from the Northern Sweden Health and Disease Study cohort, a carrier frequency could be determined for the Skelleftea and Lycksele populations. A previous study of the amyloidogenic transthyretin mutation TTRV30M in Northern Sweden's endemic area has shown a large variation in carrier frequency and penetrance of the trait within the area. However, the estimations have been based on a small sample size within the different regions in the area and therefore, the wide variation in TTRV30M carrier frequency observed between the Lycksele and Skelleftea populations are uncertain. Based on a total of 3460 samples, the estimated overall carrier frequency in the two regions was 1.82% with a carrier frequency in the Skelleftea and Lycksele population of 1.63% and 2.02%, respectively. Thus, the previously reported extremely high frequency in the Lycksele region compared to that of the Skelleftea region could not be substantiated. However, it does not change the previous finding of a surprisingly higher carrier frequency in the population from endemic area of Northern Sweden compared to that reported from endemic areas in Portugal.
TL;DR: It is demonstrated that the exposure of AS to oxidative stress induced by UV radiation (ASUV) blocks the protein fibrillation, leading to the formation of highly toxic fibril-incompetent oligomers, and suggest that specific oxidation of Met5 might be sufficient to promote theformation of highly neurotoxic oligomers of AS.
Abstract: Oxidative stress and the formation of cytotoxic aggregates of the presynaptic protein α-synuclein (AS) are two important events associated with the pathogenesis of Parkinson's disease (PD) and several other neurodegenerative diseases. In this context, extensive efforts have been made to elucidate the molecular basis of the cytotoxic synergy between oxidative stress and AS aggregation. In this study, we demonstrate that the exposure of AS to oxidative stress induced by UV radiation (ASUV) blocks the protein fibrillation, leading to the formation of highly toxic fibril-incompetent oligomers. In addition, ASUV exhibited stronger anti-fibrillogenic properties than H2O2-treated AS, inhibiting the fibrillation of unmodified AS at notably low concentrations. Mass spectrometry indicated that Met5 oxidation to Met-sulfoxide was the only modification promoted by UV exposure, which is reinforced by NMR data indicating that Met5 is the only residue whose amide resonance completely disappeared from the (1)H-(15)N HSQC spectrum after UV exposure. This result is supported by previous data that indicate that C-terminal Met residues (Met116 and Met127) and N-terminal Met1 are less susceptible to oxidation than Met5 because of the residual structure of the disordered AS monomer. Overall, our findings suggest that specific oxidation of Met5 might be sufficient to promote the formation of highly neurotoxic oligomers of AS.
TL;DR: The data indicate that when SAA protein is continuously present, depletion of phagocytic cells during the early course of the disease progression temporarily reduces amyloid load.
Abstract: Objective: Determine the role of phagocytosis in the deposition of acute phase SAA protein in peripheral organs as AA amyloid.Methods: AA amyloidosis was induced by injection of amyloid enhancing factor (AEF) in huIL-6 transgenic mice. Clodronate liposomes were injected at different times, and the amyloid load evaluated by Congo red birefringence staining and monitoring with the amyloid specific probe 125I-labeled peptide p5R.Results: Injection of clodronate containing liposomes depleted Iba-1 positive and F4/80 positive phagocytic cells in liver and spleen for up to 5 days. Treatment prior to administration of intravenous AEF did not alter the pattern of deposition of the AEF in spleen, but inhibited the catabolism of the 125I-labeled AEF. Clodronate treatment 1 day before or 1 day after AEF administration had little effect on AA amyloid accumulation at 2 weeks; however, mice treated with clodronate liposomes 5 days after AEF induction and evaluated at 2 weeks post-AEF induction showed reduced am...
TL;DR: The results suggest that triplet regimen of VMP appears to be an effective regimen in advanced AL amyloidosis, but benefits in the patients with multi-organ dysfunction remain to be proven.
Abstract: Bortezomib combination chemotherapy appears to be active in light chain (AL) amyloidosis with high rates of hematologic and organ response. We report a retrospective evaluation of the clinical outcome of treatment with bortezomib, melphalan, and prednisolone (VMP) as first-line chemotherapy in patients with AL amyloidosis who were ineligible for autologous stem cell transplant. Among the 19 patients included in this study, 90% had two or more involved organs and most of the patients had advanced stage AL amyloidosis (84% with 2004 Mayo Stage III and 92% with 2012 Mayo Stage III or IV). Sixteen (84%) patients had a hematologic response, including seven (37%) with complete response, with time to response of 1-3 months. Cardiac and renal responses were observed in 44% and 33% of patients, respectively. Estimated 2-year survival is 39%, and 5 patients (26%) died during therapy. The common grade 3-4 adverse events were thrombocytopenia, diarrhea and pneumonia. A once-weekly bortezomib is more feasible than twice-weekly regimen. Our results suggest that triplet regimen of VMP appears to be an effective regimen in advanced AL amyloidosis ,but benefits in the patients with multi-organ dysfunction remain to be proven.
TL;DR: New insights are provided into the pathogenesis of TTR-related amyloidosis that, if they were to be confirmed through experimental investigations, could significantly improve the understanding of the disease.
Abstract: Introduction: Transthyretin (TTR)-related amyloidosis is a life-threatening disease. Currently, several questions about the pathogenic mechanisms of TTR-related amyloidosis remain unanswered.Methods: We have investigated various TTR-related issues using different in silico approaches.Results: Using an amino acid similarity-based analysis, we have indicated the most relevant TTR secondary structures in determining mutation impact. Our amyloidogenic propensity analysis of TTR missense substitutions has highlighted a similar pattern for wild-type and mutated TTR amino β acid sequences. However, some mutations present differences with respect to the general distribution. We have identified non-coding variants in cis-regulatory elements of the TTR gene, and our analysis on V122I-related haplotypes has indicated differences in non-coding regulatory variants, suggesting differences among V122I carriers. The analysis of methylation status indicated CpG sites that may affect TTR expression. Finally, our in...
TL;DR: It is shown by a combination of independent techniques including electron microscopy, Thioflavin T fluorescence, and circular dichroism that GAPR-1 has the capability to form amyloid-like fibrils in the presence of liposomes containing negatively charged lipids.
Abstract: Golgi-Associated plant Pathogenesis Related protein 1 (GAPR-1) is a mammalian protein that is a member of the Cysteine-rich secretory proteins, Antigen 5 and Pathogenesis related proteins group 1 (CAP) superfamily of proteins. A role for the common CAP domain in the function of the diverse superfamily members has not been described so far. Here, we show by a combination of independent techniques including electron microscopy, Thioflavin T fluorescence, and circular dichroism that GAPR-1 has the capability to form amyloid-like fibrils in the presence of liposomes containing negatively charged lipids. Surprisingly, GAPR-1 was also shown to bind the amyloid-oligomer specific antibody A11 in the absence of lipids, indicating that GAPR-1 has an intrinsic tendency to form oligomers. This behavior is characteristic for proteins that interfere with Aβ aggregation and indeed we found that GAPR-1 effectively inhibited aggregation of Aβ(1-40) peptide. Immuno-dot blot analysis revealed that GAPR-1 binds to prefibrillar oligomeric Aβ structures during the early stages of fibril formation. Another CAP domain-containing protein, CRISP2, was also capable of forming fibrils, indicating that oligomerization and fibril formation is a shared characteristic between CAP family members. We suggest that the CAP domain may regulate protein oligomerization in a large variety of proteins that define the CAP superfamily.
TL;DR: A case of heterozygous Val122L mutated TTR-related cardiac amyloidosis treated with isolated heart transplantation with no recurrence of amyloids in the cardiac allograft and no systemic abnormalities 5 years after heart transplants is reported.
Abstract: Transthyretin (TTR) cardiac amyloidosis is characterized by deposition of either mutant or wild type TTR amyloid protein in the myocardium ultimately leading to progressive cardiomyopathy and heart failure. The most common TTR gene mutation that leads to TTR cardiac amyloidosis is the valine-to-isoleucine substitution at position 122 (V122I or Ile122). Currently, the only definitive treatment suggested for mutant TTR cardiac amyloidosis is the combined or sequential liver-heart transplantation in eligible patients, since liver is the source of TTR production. Here, we report a case of heterozygous Val122L mutated TTR-related cardiac amyloidosis treated with isolated heart transplantation with no recurrence of amyloid in the cardiac allograft and no systemic abnormalities 5 years after heart transplantation. Abbreviations MMF mycophenolate mofetil NYHA New York Heart Association TTR transthyretin VE minute ventilation.
TL;DR: It is found that an αA-crystallin-derived peptide, αA66-80 (1.8 kDa), is a prominent LMW peptide concentrated in water-insoluble fractions of the aging lens and has amyloid-like properties and preferentially insolubilizes α- Crystallin from lens-soluble fractions.
Abstract: Age-related cataract formation is marked by the progressive aggregation of lens proteins. The formation of protein aggregates in the aging lens has been shown to correlate with the progressive accumulation of a range of post-translational crystallin modifications, including oxidation, deamidation, racemization, methylation, acetylation, N- and C-terminal truncations and low molecular weight (LMW) crystallin fragments. We found that an αA-crystallin-derived peptide, αA66-80 (1.8 kDa), is a prominent LMW peptide concentrated in water-insoluble fractions of the aging lens. The peptide has amyloid-like properties and preferentially insolubilizes α-crystallin from lens-soluble fractions. It binds at multiple sites and forms a hydrophobically driven non-covalent complex with α-crystallin to induce α-crystallin aggregation. To define the specific role of the αA66-80 peptide in age-related protein aggregation and cataract formation, it is important to understand the mechanisms by which this peptide acts. ...
TL;DR: The results of AD-CSF markers including Aβ1-38 and 11C PiB-PET in the lvPPA patients demonstrate a common pathological mechanism with the occurrence of AD.
Abstract: Primary progressive aphasia (PPA) is a cognitive syndrome characterized by progressive and isolated language impairments due to neurodegenerative diseases. Recently, an international group of experts published a Consensus Classification of the three PPA clinical variants (naPPA, svPPA and lvPPA). We analyzed 24 patients with PPA by cognitive functions, neuroimaging (MRI, 99 mTc ECD-SPECT, 11C PiB-PET and FDG-PET) and cerebrospinal fluid (CSF) analysis (ptau-181, Aβ1-42, Aβ1-40 and Aβ1-38), to elucidate relationships between neuroimaging studies and biochemical findings in the three PPA clinical variants. Cognitive and speech functions were measured by mini-mental state examination and standard language test of aphasia. The patients with lvPPA showed significant decreases in CSF Aβ1-42 and ratios of Aβ1-42/Aβ1-40 and Aβ1-42/Aβ1-38, and significant increases in CSF ptau-181 and ratios of ptau-181/Aβ1-42 and ptau-181/Aβ1-38; these findings were similar to those of patients with Alzheimer’s disease (A...
TL;DR: In vitro binding of [3H]PIB to tissues containing transthyretin (ATTR), immunoglobulin light-chain (AL), amyloid protein A (AA) and Aβ is evaluated to assess Aβ deposition in brain of patients with Alzheimer’s disease (AD).
Abstract: Systemic amyloidosis is caused by extracellular deposition of insoluble fibrillar proteins arranged in β-pleated sheets. [11C]PIB has been used in PET studies to assess Aβ deposition in brain of patients with Alzheimer’s disease (AD). The possibility to visualize other types of amyloid deposits with [11C]PIB would be of potential clinical importance in early diagnosis and for following therapeutic effects. In the present study, we evaluated in vitro binding of [3H]PIB to tissues containing transthyretin (ATTR), immunoglobulin light-chain (AL), amyloid protein A (AA) and Aβ amyloid. We found significantly higher binding of [3H]PIB in tissue from systemic amyloidoses than in control tissue, i.e. 4.7 times higher (p < 0.05). [3H]PIB showed the highest affinity to cortex of AD brain (IC50 = 3.84 nM), while IC50 values were much higher for ATTR, AA and AL type of amyloidosis and large variations in affinity were observed even within tissues having the same type of amyloidosis. Extraction with guanidine...
TL;DR: It is demonstrated that OPN appears to be a valuable marker in the clinical routine for evaluation of patients with AL amyloidosis, especially if it is used in combination with cTNT and/or NT-proBNP.
Abstract: Background: Troponin-T (cTnT) and NT-proBNP provide prognostic information in light-chain amyloidosis (AL). Thus, these biomarkers are widely used in clinical routine for risk stratification. Recently, plasma level of osteopontin (OPN), a secreted phosphoglycoprotein expressed by a variety of cell types, has been reported as a risk predictor in various cardiovascular diseases.Methods: OPN was determined retrospectively in 150 consecutive patients newly diagnosed with AL amyloidosis. All patients were evaluated according to a routine protocol including electrocardiography, echocardiography and laboratory testing.Results: Mean OPN was 591 ± 37 ng/mL. Cardiac involvement was established in 83 (55.3%). Median OPN plasma level were associated with number of organs involved, renal function, eligibility for high-dose melphalan chemotherapy and autologous stem cell transplantation, and severity of cardiac amyloidosis. Median follow-up was 19.2 months. 1-year all-cause-survival was 83.4%. The cut-offs disc...
TL;DR: Plerixafor was effective and well tolerated when used upfront or as rescue for PBSC mobilization in AL amyloidosis patients with cardiac involvement, and has non-overlapping toxicities with G-CSF.
Abstract: Nearly half of AL amyloidosis patients have cardiac involvement, an independent predictor of poor prognosis. High-dose melphalan and autologous stem-cell transplantation (HDM/SCT) can induce complete hematologic responses and prolong survival in AL amyloidosis. Granulocyte colony-stimulating factor (G-CSF)-induced mobilization of peripheral blood stem cell (PBSC) in AL amyloidosis patients is associated with volume overload, arrhythmias and capillary leak syndrome. Plerixafor has a different mechanism of action and has non-overlapping toxicities with G-CSF. We describe our experience in five patients with AL amyloidosis and cardiac involvement who received plerixafor with G-CSF for PBSC mobilization. Median age was 56 years; two patients had undergone heart transplantation within the year prior to HDM/SCT. Three patients received plerixafor after an initial trial of mobilization with G-CSF alone. No patient had any significant toxicities during mobilization and PBSC collection. The median total yi...
TL;DR: Troponin I is more accurate and seems to be the best biohumoral marker of RV dysfunction, which is able to identify a subgroup of AL patients with RV dysfunction.
Abstract: Aim: In AL amyloidosis, the importance of right ventricle (RV) involvement has recently been underlined and its role in predicting prognosis has been emphasized. Little is known about the relationship between RV involvement, N-terminal pro-brain natriuretic peptide (NT-proBNP) and troponin levels. Aim of our study was to clarify the relationship between NT-proBNP and troponin and RV involvement and analyze their independent value as predictors of RV dysfunction.Methods and Results: We examined 76 consecutive patients with biopsy-proven AL amyloidosis. Each patient received complete clinical evaluation, troponin I, NT-proBNP assay and comprehensive echocardiographic evaluation. Considering a tricuspidal annulus plane systolic excursion (TAPSE) value <16 mm, 23 patients (30%) presented RV systolic dysfunction, whereas 53 (70%) did not. Patient with reduced TAPSE had thicker left ventricle (LV) walls and RV free walls, reduced LV fractional shortening, impaired LV diastolic function and worse LV and ...
TL;DR: It is found that ApoE increases cell association of Aβ in a HSPG- and LRP1-dependent manner; and further,ApoE processing is altered in the absence of cellular HS, which may facilitate Aβ clearance from the brain, but if overwhelmed could contribute to Aβ accumulation and the pathogenesis of AD.
Abstract: The increased risk of Alzheimer's disease (AD) associated with specific apolipoprotein E (ApoE) isoforms appears to relate to altered amyloid-β (Aβ) homeostasis. Clearance of Aβ from the brain is reduced in the presence of the AD-associated ApoE4 isoform, which may contribute to the accumulation of Aβ deposits in the parenchyma and vasculature. The low-density lipoprotein receptor-related protein 1 (LRP1) and heparan sulfate proteoglycans (HSPGs), both established ApoE receptors, are involved in Aβ uptake, with LRP1 additionally implicated in Aβ transcytosis across the blood-brain barrier. In this study, we detected the co-distribution of heparan sulfate (HS), ApoE and LRP1 in Aβ(1-40)-positive brain microvessels from individuals with Down's syndrome diagnosed with AD. In addition, ApoE was pulled-down from AD cerebrospinal fluid with anti-Aβ antibodies. Using Chinese hamster ovary cells deficient in HS or LRP1, we found that ApoE increases cell association of Aβ in a HSPG- and LRP1-dependent manner; and further, ApoE processing is altered in the absence of cellular HS. These interactions may facilitate Aβ clearance from the brain, but if overwhelmed could contribute to Aβ accumulation and the pathogenesis of AD.
TL;DR: The aim of this study was to elucidate how the genetic profile of the liver is affected by the disease, and how amyloid deposits affect target tissue.
Abstract: Introduction: Hereditary transthyretin amyloidosis (ATTR) is a genetic disease caused by a point mutation in the TTR gene that causes the liver to produce an unstable TTR protein. The most effectiv ...
TL;DR: Transthyretin-related amyloidosis (ATTR) as discussed by the authors is an autosomal-dominant neurodegenerative disorder (i.e. hereditary amyloids).
Abstract: Transthyretin-related amyloidosis (ATTR amyloidosis) is an autosomal-dominant neurodegenerative amyloid disorder (i.e. hereditary amyloidosis). The subtype of hereditary amyloidosis is defined by t...
TL;DR: This large cohort of individuals carrying the TTRVal20Ile mutation reveals a predominantly cardiac phenotype with high penetrance and late onset of symptoms.
Abstract: Background: Transthyretin-related amyloidosis (ATTR) is characterized by a wide heterogeneity of genotypes and predominantly neurological and cardiac phenotypes. This study aims to characterize a cohort of patients with the rare transthyretin (TTR) Val20Ile (p.TTRVal40Ile) variant.Methods and results: This study comprises a single-center cohort of 59 individuals subsequently evaluated for TTRVal20Ile variant due to clinical (n = 13) or predictive (n = 46) reasons. All patients were mainly related to Wagshurst, a small village in the South of Germany. Clinical assessment was performed by neurological evaluation, echocardiography, electrocardiography, cardiac biomarkers, cardiac MRI (n = 13), and 99mTc-DPD scintigraphy (n = 16). The rare TTRVal20Ile variant was found in 41 patients; evidence of cardiac amyloidosis was present in 22 patients. Evidence of pulmonary involvement was obtained by 99mTc-DPD scintigraphy in eight patients. No further organ involvement was observed in any of the patients car...
TL;DR: Through a literature review, it was found that the TTR Gly83Arg mutant which was only reported in Chinese patients may be an important indication of solitary ocular vitreous amyloidosis without evidence of systemic involvement and was the most frequent cause of adult-onset vitreously amyloidsosis in Chinese people.
Abstract: We would like to report close on two sisters with recurrent vitreous involvement after vitrectomy and the need of subsequent surgical reintervention prompted the diagnosis of a TTR-related, familia...
TL;DR: This first detailed immunohistological analysis of MM-associated amyloid arthropathy suggests that it is a chronic synovitis that evolves despite the loss of humoral immunity seen in advanced MM.
Abstract: Objectives: To describe histological, immunohistochemical and ultrastructural features of synovial biopsies of amyloid arthropathy associated with multiple myeloma (MM).Methods: Synovial biopsies from affected joints of two patients with MM and amyloid arthropathy were examined with light and electron microscopy, and immunohistochemically for expression of CD3, CD8, CD20, CD38, CD68, Ki-67 and vWF. Results were compared to values from osteoarthritis (OA, n = 26), rheumatoid arthritis (RA, n = 24) and normal (n = 15) synovial membranes.Results: There was no or only mild lining hyperplasia. Vascular density was not elevated, and there were few Ki-67+ proliferating cells in the stroma. The Krenn synovitis score classified one specimen as “low-grade” and one as “high-grade” synovitis. CD68+ and CD3+ cells were the predominant mononuclear inflammatory cells, whereas CD20+ and CD38+ cells were absent from both synovial membrane and synovial fluid sediment. Electron microscopy demonstrated amyloid phagoc...