Showing papers in "Amyloid in 2021"
TL;DR: In 2012, the International Society of Amyloidosis (ISA) established the criteria for assessment of haematologic response to treatment in light chain amyloids as discussed by the authors.
Abstract: In 2012, the International Society of Amyloidosis (ISA) established the criteria for assessment of haematologic response to treatment in light chain (AL) amyloidosis [1]. The criteria were identifi...
52 citations
TL;DR: Prevalence and incidence rate of AEs was high in a large, multicentric, real-world cohort of cardiac amyloidosis, and a consistent proportion of events occurred despite anticoagulation therapy or in patients in sinus rhythm.
Abstract: Intracardiac thrombosis is reported to occur frequently in cardiac amyloidosis (CA). However, data regarding arterial thrombo-embolic events (AEs) in CA are limited. We aimed at assessing prevalenc...
32 citations
TL;DR: In this article, the authors provide a comprehensive assessment of eligibility criteria, stem cell collection and mobilisation strategies and regimens, risk-adapted melphalan dosing, role for induction and consolidation therapies, specific supportive care management, long-term outcome with respect to survival, haematologic response and relapse and organ responses following stem cell transplantation.
Abstract: AL amyloidosis is a systemic amyloidosis and is associated with an underlying plasma cell dyscrasia. High dose intravenous melphalan and autologous stem cell transplantation was developed for the treatment of AL amyloidosis in the early 1990s and was prompted by its success in multiple myeloma. This application has evolved significantly over the past three decades. These guidelines provide a comprehensive assessment of eligibility criteria, stem cell collection and mobilisation strategies and regimens, risk-adapted melphalan dosing, role for induction and consolidation therapies, specific supportive care management, long-term outcome with respect to survival, haematologic response and relapse and organ responses following stem cell transplantation. These guidelines are developed by the experts in the field on behalf of the stem cell transplant working group of the International Society of Amyloidosis (ISA) and European Haematology Association (EHA).
31 citations
TL;DR: Patients with ATTR-CA and AF are at increased risk for stroke compared to patients with AT transthyretin cardiac amyloidosis and without AF, and thrombotic events and major bleeds did not differ between those who received warfarin and NOACs.
Abstract: Atrial fibrillation (AF) is common in patients with transthyretin cardiac amyloidosis (ATTR-CA). The optimal strategy to prevent strokes in patients with ATTR-CA and AF is unknown. To compare outco...
29 citations
Indiana University1, Boston University2, Mayo Clinic3, Paris 12 Val de Marne University4, University College London5, University Medical Center Groningen6, University of Pavia7, Loyola University Medical Center8, University of Kiel9, University Hospital Heidelberg10, Kumamoto University11, Uppsala University12
TL;DR: In this article, the authors describe methods employed at some laboratories specialised in amyloidosis in Europe, Japan and USA, in order to determine the biochemical fibril nature.
Abstract: A reliable diagnosis of amyloidosis is usually based on a tissue biopsy. With increasing options for specific treatments of the different amyloid diseases, an exact and valid diagnosis including determination of the biochemical fibril nature is imperative. Biopsy sites as well as amyloid typing principles vary and this paper describes methods employed at some laboratories specialised in amyloidosis in Europe, Japan and USA.
22 citations
TL;DR: The potency similarities revealed by the study suggest that differences in safety, adsorption and metabolism, pharmacokinetics, and tissue distribution become important for kinetic stabiliser clinical use decisions.
Abstract: Transthyretin (TTR) tetramer dissociation is rate limiting for aggregation and subunit exchange. Slowing of TTR tetramer dissociation via kinetic stabiliser binding slows cardiomyopathy progression...
21 citations
TL;DR: Using sensitive next-generation flow cytometry (NGF) to detect minimal residual disease (MRD) in AL amyloidosis patients at complete haematologic response has profound clinical implications, so that AL patients with undetectable MRD have a very high probability of organ response and a very low probability of haem atologic relapse.
Abstract: The treatment of AL amyloidosis aims to eradicate the plasma cell clone and eliminate toxic free light chain production. Only in a minority of patients the plasma cell clone is completely eradicate...
19 citations
TL;DR: In this article, a serum neurofilament light chain (sNfL) was found to increase in amyloid light chain in AL patients with and without polyneuropathy.
Abstract: To study serum neurofilament light chain (sNfL) in amyloid light chain (AL) amyloidosis patients with and without polyneuropathy (PNP) and to corroborate previous observations that sNfL is increase...
18 citations
TL;DR: In patients with AL amyloidosis, a very rapid and deep response is crucial, especially for those at high risk, targeting very low FLC levels within the first month of therapy.
Abstract: A rapid and deep haematologic response is fundamental in order to improve outcomes of patients with AL amyloidosis. We evaluated the impact of timing and depth of haematologic response at early time points (at 1 and 3 months from the start of therapy) in 227 consecutive previously untreated AL patients, who received bortezomib-based primary therapy. After 1 month of therapy, 30.5% had ≥VGPR, 28% PR and 36% no response (NR), with 11% having iFLC <20 mg/L and 15% dFLC <10 mg/L. Deep haematologic response at 1 month (either ≥VGPR or iFLC <20 mg/L or dFLC <10 mg/L), was associated with a high organ response rate. The survival of patients with ≥VGPR was significantly better than those with PR and NR at 1-month landmark (p < .001) but this benefit was mainly driven by those with iFLC <20 mg/L. The depth of haematologic response at 1 month was significant across all Mayo stages. At 3 months, 46% of the patients had not significantly improved the depth of their response but even patients that improved their response from an iFLC ≥20 mg/L at 1 month to iFLC <20 mg/L at 3 months still had inferior outcome to those with an early deep response. Thus, in patients with AL amyloidosis, a very rapid and deep response is crucial, especially for those at high risk, targeting very low FLC levels within the first month of therapy.
18 citations
TL;DR: This article showed that ex vivo fibrils from patient or animal tissue were structurally different from in-vivo formed fibril from the same polypeptide chain, which supported the idea of a proteolytic selection of pathogenic amyloid Fibril morphologies.
Abstract: Several studies recently showed that ex vivo fibrils from patient or animal tissue were structurally different from in vitro formed fibrils from the same polypeptide chain. Analysis of serum amyloid A (SAA) and Aβ-derived amyloid fibrils additionally revealed that ex vivo fibrils were more protease stable than in vitro fibrils. These observations gave rise to the proteolytic selection hypothesis that suggested that disease-associated amyloid fibrils were selected inside the body by their ability to resist endogenous clearance mechanisms. We here show, for more than twenty different fibril samples, that ex vivo fibrils are more protease stable than in vitro fibrils. These data support the idea of a proteolytic selection of pathogenic amyloid fibril morphologies and help to explain why only few amino acid sequences lead to amyloid diseases, although many, if not all, polypeptide chains can form amyloid fibrils in vitro.
17 citations
TL;DR: In this article, wild-type tranthyretin amyloid (ATTR) was found to play a role in carpal tunnel syndrome (CTS) and spinal stenosis (SS) in cardiac tissue.
Abstract: Age-related cardiac amyloidosis results from deposits of wild-type tranthyretin amyloid (ATTRwt) in cardiac tissue. ATTR may play a role in carpal tunnel syndrome (CTS) and in spinal stenosis (SS),...
TL;DR: Cerebral amyloid angiopathy is a small vessel disease, causing spontaneous intracerebral hemorrhage in the elderly, and strongly associated with Alzheimer disease (AD).
Abstract: Cerebral amyloid angiopathy (CAA) is a small vessel disease, causing spontaneous intracerebral hemorrhage (ICH) in the elderly. It is strongly associated with Alzheimer disease (AD), with which it ...
TL;DR: Overall, gender seems to be a factor that substantially modulates the AO of the disease, in this area, as well as penetrance, which is increased in case of maternal inheritance and in male patients.
Abstract: INTRODUCTION Hereditary transthyretin (ATTRv) amyloidosis is of autosomal dominant transmission, caused by a spectrum of mutations in the transthyretin (TTR) gene. The ATTRV30M (p.Val50Met) is the most frequent substitution in Europe. Northern Sweden is a known cluster for ATTRV30M amyloidosis patients due to high prevalence of the mutation rate, with homozygous cases. First symptoms occur generally during the 6th decade. Previous studies reported low penetrance in this area and possible anticipation in families. In order to refine our knowledge of the genetic aspects, penetrance and factors that influence the disease's risk, we performed a comprehensive study of ATTRV30M families in Sweden. METHODS To assess anticipation, well-established age at onset (AO) was compared in all informative parent-offspring pairs and in subgroups, after excluding ascertainment biases. Penetrance was estimated using a non-parametric method that enables to study covariates' effect on the disease's risk. RESULTS We analysed 114 ATTRV30M Swedish families, including 12 homozygous individuals. Among 131 parent-offspring pairs, we found an average anticipation of 11.7 [Standard Deviation (SD) =10.03] years, higher in case of maternal transmission (mean ± SD = 13.7 ± 8.4 years), compared to paternal transmission (mean ± SD = 7.9 ± 11.5 years, p < .003). Anticipation remained significant, after exclusion of ascertainment biases. In heterozygous ATTRV30M kindred, penetrance was low, estimated below 10% [95% confidence interval (CI) = 6-10] at 40 years-old, increasing to 71% [95% CI= 65-76] at age 90 years. The risk was found to be higher in male patients (p < .01) and in case of maternal transmission (p < .01), reflecting a parent of origin effect. We observed no difference of penetrance according the geographical origin. Finally, the disease risk was similar in heterozygous and homozygous ATTRV30M amyloidosis individuals. CONCLUSIONS Our study provides new data on the genetics of ATTRV30M families in Sweden, including the occurrence of anticipation and on penetrance. Both are increased in case of maternal inheritance and in male patients. Overall, gender seems to be a factor that substantially modulates the AO of the disease, in this area. Clinically, these findings are of importance to guide the management of sibships and the monitoring of mutation carriers.
TL;DR: In this paper, the authors examined the regional incidence of new light-chain amyloidosis (AL) diagnosings and found that AL is considered a rare disease, although few studies have assessed its epidemiology.
Abstract: Light-chain amyloidosis (AL) is considered a rare disease, although few studies have assessed its epidemiology. Therefore, we felt it appropriate to examine the regional incidence of new AL diagnos...
TL;DR: OCT-A may play a role in the evaluation of ATTRv patients oculopathy and the effectiveness of future eye targeting treatments, as early changes in retinal vessels in ATTRV amyloidosis are identified for the first time and in vivo.
Abstract: Retinal angiopathy is a known ocular manifestation of hereditary transthyretin amyloidosis (ATTRv). Optical coherence tomography angiography (OCT-A) is a recent noninvasive imaging technique, used ...
TL;DR: In non-endemic, mostly late-onset ATTRv-PN, cardiac involvement assessed by NT-proBNP is a strong prognosticator for overall survival and long-term treatment with tafamidis is safe and efficacious.
Abstract: Hereditary transthyretin amyloidosis is caused by pathogenic variants in the TTR gene and typically manifests, alongside cardiac and other organ dysfunctions, with a rapidly progressive sensorimoto...
TL;DR: In this article, a multidisciplinary core dataset (CD) and disease severity scoring (DSS) tools were proposed for hereditary transthyretin (ATTRv) amyloidosis.
Abstract: BACKGROUND: Hereditary transthyretin (ATTRv) amyloidosis is a progressive multisystemic disease of adult-onset that arises from an inherited mutation in the transthyretin gene. Currently available disease severity and progression evaluation tools only cover one single organ or system, impacting data collection uniformity and its use in clinical settings. METHODS: The Jandhyala Method, including a systematic literature review and SMART interviews, was used to observe expert opinion from eight leaders in the treatment of ATTRv across Europe. The aim was to propose a multidisciplinary core dataset (CD) and disease severity scoring (DSS) tools. RESULTS: The multidisciplinary team of experts identified 140 indicators that form part of the standard diagnostic and monitoring practice (SDMP) and should be collected as the ATTRv CD. Thirty-one (22%) of these indicators informed disease severity and comprised the ATTRv DSS, whilst 25 (18%) were deemed to monitor disease progression. CONCLUSIONS: The resulting CD and DSS have different purposes. The ATTRv CD supports the collection of high-quality data for clinical research, whereas the ATTRv DSS can be rapidly conducted in a clinical setting and aid patient management.
TL;DR: This study reports mass spectrometry-based proteomic analysis of the protein composition of localised cutaneous amyloid deposits from seven patients using laser microdissection and shows that basal keratins are the main constituents of the amyloids deposits.
Abstract: Lichen or macular localised cutaneous amyloidoses have long been described as keratinic amyloidoses and believed to be due to the deposition of cytokeratin peptides originating from epidermis in the dermal papillae. However, recently it was suggested that galectin-7 is the causative protein for this type of amyloidosis. This was based on the detection of galectin-7 in a biopsy from a patient diagnosed with Bowen's disease and localised cutaneous amyloidosis. In this study we report mass spectrometry-based proteomic analysis of the protein composition of localised cutaneous amyloid deposits from seven patients using laser microdissection and show that basal keratins are the main constituents of the amyloid deposits. Galectin-7 was not present in the dermal amyloid deposits and was only present in the overlying Congo red negative epidermis.
TL;DR: In this paper, the authors used as a consolidation a short course of daratumumab in 25 patients with AL amyloidosis or light chain depos... and found that the combination has major and rapid activity with favorable toxicity.
Abstract: Daratumumab has major and rapid activity in AL amyloidosis with favourable toxicity. We used as a consolidation a short course of daratumumab in 25 patients with AL amyloidosis or light chain depos...
TL;DR: In this paper, the authors investigated the clinicopathological features of sporadic amyloid transthyretin (ATTR) amylodysplasticosis in 1698 serial Japanese forensic autopsy patients.
Abstract: To investigate the clinicopathological features of sporadic amyloid transthyretin (ATTR) amyloidosis.We evaluated 1698 serial Japanese forensic autopsy patients. The extent and amount of ATTR depos...
TL;DR: This is the first case of DRA associated with a naturally occurring β2-microglobulin variant, and it is noteworthy that the V27M and D76N variants show substantial differences in both clinical phenotypes and pathomechanical features.
Abstract: Till date, there had been no reported case of dialysis-related amyloidosis (DRA) associated with a β2-microglobulin variant. We report here a 41-year-old haemodialysis patient with systemic amyloidosis, exhibiting macroglossia and swelling salivary glands, uncommon clinical manifestations for DRA. Molecular analysis showed that the patient had a new variant of β2-microglobulin (V27M). Extracted amyloid protein was predominantly composed of variant β2-microglobulin. In vitro analysis revealed that this variant β2-microglobulin had a strong amyloidogenic propensity, probably owing to the decreased stability caused by a bulky methionine residue. Our data clearly show that V27M variant is amyloidogenic and this mutation results in unusual clinical manifestations. To date, only one amyloidogenic β2-microglobulin variant (D76N) has been reported in non-dialysis patients. It is noteworthy that the V27M and D76N variants show substantial differences in both clinical phenotypes and pathomechanical features. This is the first case of DRA associated with a naturally occurring β2-microglobulin variant.
TL;DR: It is shown that both purified full-length TDP-43 and its C-terminal domain possess a largely disordered secondary structure, as ascertained by far-UV circular dichroism and Fourier transform infra-red spectroscopy, indicating the absence of a clear amyloid-like signature.
Abstract: Accumulation of ubiquitin-positive, tau- and α-synuclein-negative intracellular inclusions of TDP-43 in the central nervous system represents the major hallmark correlated to amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U). Such inclusions have variably been described as amorphous aggregates or more structured deposits having amyloid properties. Here we have purified full-length TDP-43 (FL TDP-43) and its C-terminal domain (Ct TDP-43) to investigate the morphological, structural and tinctorial features of aggregates formed in vitro by them at pH 7.4 and 37 °C. AFM images indicate that both protein variants show a tendency to form filaments. Moreover, we show that both FL TDP-43 and Ct TDP-43 filaments possess a largely disordered secondary structure, as ascertained by far-UV circular dichroism and Fourier transform infra-red spectroscopy, do not bind Congo red and induce a very weak increase of thioflavin T fluorescence, indicating the absence of a clear amyloid-like signature.
TL;DR: Electrocardiographic findings in AGel amyloidosis and their relation to cardiac magnetic resonance (CMR) changes are focused on, explaining conduction disorders, although pacemaker therapy is rarely required.
Abstract: Finnish gelsolin amyloidosis (AGel amyloidosis) is an inherited systemic amyloidosis with well-known ophthalmological, neurological and cutaneous symptoms. Additionally, cardiomyopathies, conductio...
TL;DR: It is demonstrated that low disease burden AL patients who are eligible for ASCT may benefit from bortezomib-based induction therapy, and baseline dFLC > 50 mg/L was associated with worse survival, but induction with bortzomib wasassociated with better survival.
Abstract: Background Induction therapy is recommended before autologous stem cell transplantation (ASCT) for AL amyloidosis patients with high disease burden [bone marrow plasma cells (BMPCs) > 10%], but the role of induction therapy before ASCT in patients with low disease burden (BMPCs ≤ 10%) is still unknown. Methods A total of 227 patients with AL amyloidosis were included in this study. Among 227 patients, 124 patients received bortezomib-based induction prior to ASCT and were defined as group A, 35 patients received other chemotherapeutic induction and were defined as group B, and the other 68 patients without induction were defined as group C. We compared the differences of efficacy and prognosis between the three groups. Results The haematological overall response rates (ORR) of groups A, B and C were 91%, 67% and 75%, respectively. The complete response rates (CR) of groups A, B and C were 50%, 25% and 20%, respectively. Both the ORR and CR rates of group A were significantly higher than those of groups B and C. The renal response rates of groups A, B and C were 64%, 46% and 47%, respectively. The cardiac response rates of groups A, B and C were 74%, 45% and 40%, respectively. The renal and cardiac responses rates of group A were also significantly higher than those of the other two groups. After a median follow-up of 44 months, the median OS was not reached. The 5-year estimated overall survival (OS) rates of groups A, B and C were 81%, 57% and 67%, respectively. The median progression-free survival (PFS) was 83 months for all patients. The 5-year estimated PFS rates of groups A, B and C were 61%, 38% and 49%, respectively. Both the OS and PFS of group A were higher than those of both group B and group C. On multivariate analysis, baseline dFLC > 50 mg/L was associated with worse survival, but induction with bortezomib was associated with better survival. Conclusion Our study demonstrated that low disease burden AL patients who are eligible for ASCT may benefit from bortezomib-based induction therapy.
TL;DR: In this article, untargeted metabolomics is a well-established technique and a powerful tool to find potential plasma biomarkers for early diagnosing hereditary transthyretin amyloidosis.
Abstract: Untargeted metabolomics is a well-established technique and a powerful tool to find potential plasma biomarkers for early diagnosing hereditary transthyretin amyloidosis. Hereditary transthyretin a...
TL;DR: In this article, endocular amyloid deposition in hereditary transthyretin AMyloidosis (hATTR) is a significant cause of morbidity in these patients.
Abstract: Endocular amyloid deposition in hereditary transthyretin amyloidosis (hATTR) is a significant cause of morbidity in these patients. Vitreous opacities lead to vision loss and are a well recognise c...
TL;DR: In this paper, amyloid light-chain (AL)-CA and transthyretin (ATTR)-CA were matched in patients with cardiac amyloids.
Abstract: Neurohormonal activation has never been investigated in patients with cardiac amyloidosis (CA).Forty-seven patients with amyloid light-chain (AL)-CA and 61 with transthyretin (ATTR)-CA were matched...
TL;DR: Recently, epidermal growth factor (EGF)-containing fibulin-like extracellular matrix protein 1 (EFEMP1) has been reported in humans as mentioned in this paper, which is a precursor protein for amyloid precursor proteins.
Abstract: Until now, more than 36 amyloid precursor proteins have been reported in humans [1]. Recently, epidermal growth factor (EGF)-containing fibulin-like extracellular matrix protein 1 (EFEMP1), also kn...
TL;DR: V30M in transthyretin (TTR) gene is causative for hereditary ATTRv amyloidosis (familial Amyloid polyneuropathy) as mentioned in this paper.
Abstract: V30M in transthyretin (TTR) gene is causative for hereditary ATTRv amyloidosis (familial amyloid polyneuropathy). ATTRv amyloidosis shows a wide variation in age-at-onset (AO) between clusters, fam...
TL;DR: A case of localised amyloid deposition in association with neuroendocrine tumours, such as medullary thyroid carcinoma and pituitary prolactinoma is reported.
Abstract: Localised amyloid deposition sometimes occurs in association with neuroendocrine tumours (NET), such as medullary thyroid carcinoma and pituitary prolactinoma. Here, we report a case of localised a...