-
The Journal of Biological Chemistry Apr 2024AL amyloidosis is a life-threatening disease caused by deposition of immunoglobulin light chains. While the mechanisms underlying light chains amyloidogenesis in vivo...
AL amyloidosis is a life-threatening disease caused by deposition of immunoglobulin light chains. While the mechanisms underlying light chains amyloidogenesis in vivo remain unclear, several studies have highlighted the role that tissue environment and structural amyloidogenicity of individual light chains have in the disease pathogenesis. AL natural deposits contain both full-length light chains and fragments encompassing the variable domain (V) as well as different length segments of the constant region (C), thus highlighting the relevance that proteolysis may have in the fibrillogenesis pathway. Here, we investigate the role of major truncated species of the disease-associated AL55 light chain that were previously identified in natural deposits. Specifically, we study structure, molecular dynamics, thermal stability, and capacity to form fibrils of a fragment containing both the V and part of the C (133-AL55), in comparison with the full-length protein and its variable domain alone, under shear stress and physiological conditions. Whereas the full-length light chain forms exclusively amorphous aggregates, both fragments generate fibrils, although, with different kinetics, aggregate structure, and interplay with the unfragmented protein. More specifically, the V-C 133-AL55 fragment entirely converts into amyloid fibrils microscopically and spectroscopically similar to their ex vivo counterpart and increases the amorphous aggregation of full-length AL55. Overall, our data support the idea that light chain structure and proteolysis are both relevant for amyloidogenesis in vivo and provide a novel biocompatible model of light chain fibrillogenesis suitable for future mechanistic studies.
Topics: Amyloid; Humans; Immunoglobulin Light Chains; Molecular Dynamics Simulation; Immunoglobulin Constant Regions; Immunoglobulin Light-chain Amyloidosis; Kinetics; Protein Domains
PubMed: 38499153
DOI: 10.1016/j.jbc.2024.107174 -
Alzheimer's Research & Therapy Oct 2023In MAPT (Multidomain Alzheimer Preventive Trial), a cognitive effect of multidomain intervention (MI) was showed in non-demented subjects with positive amyloid PET.... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
In MAPT (Multidomain Alzheimer Preventive Trial), a cognitive effect of multidomain intervention (MI) was showed in non-demented subjects with positive amyloid PET. However, screening eligible patients for multidomain intervention by PET is difficult to generalize in real-world settings.
METHODS
MAPT study was a 3-year, randomized, placebo-controlled trial followed by a 2-year observational and optional extension. All participants were non-demented and randomly assigned (1:1:1:1) to the MI plus omega 3, MI plus placebo, omega 3 alone, or placebo alone group. The objectives were to assess the cognitive effect of MAPT interventions (omega 3 supplementation, MI, combined intervention) in non-demented subjects according to amyloid blood status at 12, 36, and 60 months. In this subgroup analysis (n = 483), amyloid status was defined by plasma Aβ42/40 ratio (cutoff ≤ 0.0107). The primary outcome measure was the change in cognitive composite score after a 1, 3, and 5-year clinical follow-up.
RESULTS
The intention-to-treat (ITT) population included 483 subjects (161 positive and 322 negative amyloid participants based on plasma Aβ42/40 ratio). In the positive amyloid ITT population, we showed a positive effect of MI plus omega 3 on the change in composite cognitive score in 12 (raw p = .0350, 0.01917, 95% CI = [0.0136 to 0.3699]) and 36 months (raw p = .0357, 0.2818, 95% CI = [0.0190 to 0.5446]). After correction of multiple comparisons and adjustments, these differences were not significant (adjusted p = .1144 and .0690). In the per-protocol positive amyloid group (n = 154), we observed a significant difference between the combined intervention and placebo groups at 12 (p = .0313, 0.2424, 0.0571 to 0.4276) and 36 months (p = .0195, 0.3747, 0.1055 to 0.6439) persisting after adjustment. In the ITT and per-protocol analyses, no cognitive effect was observed in the positive and negative amyloid group at 60-month visit.
CONCLUSIONS
These findings suggest a benefit of MI plus omega 3 in positive blood amyloid subjects. This promising trend needs to be confirmed before using blood biomarkers for screening in preventive trials.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT01513252 .
Topics: Humans; Alzheimer Disease; Fatty Acids, Omega-3; Research Design; Amyloid; Cognition
PubMed: 37872582
DOI: 10.1186/s13195-023-01325-3 -
Journal of Surgical Case Reports May 2024Primary amyloidosis of the conjunctiva and eyelid is a rare and often misdiagnosed condition. It is characterized by the deposition of insoluble amyloid fibrils, which...
Primary amyloidosis of the conjunctiva and eyelid is a rare and often misdiagnosed condition. It is characterized by the deposition of insoluble amyloid fibrils, which are misfolded proteins, in the body. Amyloidosis can be systemic or localized with different types of amyloid fibril proteins identified using mass spectrometry. Ocular involvement in amyloidosis can lead to corneal dystrophies, glaucoma, vitreous opacities, and other symptoms. Diagnosis involves clinical examination and histopathological assessment. Treatment options depend on the extent of involvement and may include surgical excision, glaucoma management, vitrectomy, or liver transplantation in rare cases. We present a rare case of localized conjunctival amyloidosis initially misdiagnosed as pyogenic granuloma, with clinical symptoms of ptosis, periorbital swelling, and conjunctival lesions. The patient underwent excision of the lesions, and subsequent evaluation did not reveal systemic amyloidosis. Ocular amyloidosis requires careful diagnosis and consideration of systemic involvement for appropriate management.
PubMed: 38817793
DOI: 10.1093/jscr/rjae356 -
Lakartidningen May 2024Technical developments have paved the way for the development of ultrasensitive analytical methods that allow for precise quantification of brain-specific proteins in... (Review)
Review
Technical developments have paved the way for the development of ultrasensitive analytical methods that allow for precise quantification of brain-specific proteins in blood samples. Plasma levels of amyloid β, specifically the Aβ42/40 ratio, are reduced in Alzheimer's disease (AD) and show concordance with brain amyloidosis assessed by PET, but the overlap with normal elderly may be too large for reliable use in clinical applications. Plasma phosphorylated tau (P-tau), especially a variant called P-tau217, is markedly increased in the early symptomatic stages of AD but remains normal in other neurodegenerative disorders. Total tau (T-tau) is measurable in blood and shows most promise as a biomarker for acute neuronal injury (e.g. acute traumatic or hypoxic brain injury), where T-tau shows a fast and dramatic increase but does not work well as an AD biomarker due to contributions to blood levels from peripheral tissues. Instead, a novel method for tau protein produced only in the CNS called brain-derived tau (BD-tau) shows promise as a biomarker for AD-type neurodegeneration. Neurofilament light (NFL) levels in blood correlate tightly with levels in CSF and reflect axonal injury irrespective of the underlying cause. Increased blood NFL concentration is found in several neurodegenerative disorders, including AD, but even more so in disorders such as motor neuron disease and frontotemporal dementia. Glial fibrillary acidic protein (GFAP) is expressed with activation of astrocytes, and is mildly increased in AD, but is also very high also in acute brain disorders. These blood tests show promise as tools to identify AD pathophysiology in the first assessment of patients with early cognitive symptoms, also in primary care, to guide clinical management and possible admission to the specialist clinic. A two-step model will result in a very high accuracy to either predict or exclude brain amyloidosis of the Alzheimer type.
Topics: Humans; Alzheimer Disease; Biomarkers; tau Proteins; Amyloid beta-Peptides; Brain; Neurofilament Proteins; Glial Fibrillary Acidic Protein
PubMed: 38818759
DOI: No ID Found -
Frontiers in Immunology 2023Systemic amyloidosis is a progressive disorder characterized by the extracellular deposition of amyloid fibrils and accessory proteins in visceral organs and tissues....
INTRODUCTION
Systemic amyloidosis is a progressive disorder characterized by the extracellular deposition of amyloid fibrils and accessory proteins in visceral organs and tissues. Amyloid accumulation causes organ dysfunction and is not generally cleared by the immune system. Current treatment focuses on reducing amyloid precursor protein synthesis and slowing amyloid deposition. However, curative interventions will likely also require removal of preexisting amyloid deposits to restore organ function. Here we describe a prototypic pan-amyloid binding peptide-antibody fusion molecule (mIgp5) that enhances macrophage uptake of amyloid.
METHODS
The murine IgG1-IgG2a hybrid immunoglobulin with a pan amyloid-reactive peptide, p5, fused genetically to the N-terminal of the immunoglobulin light chain was synthesized in HEK293T/17 cells. The binding of the p5 peptide moiety was assayed using synthetic amyloid-like fibrils, human amyloid extracts and amyloid-laden tissues as substrates. Binding of radioiodinated mIgp5 with amyloid deposits was evaluated in a murine model of AA amyloidosis using small animal imaging and microautoradiography. The bioactivity of mIgp5 was assessed in complement fixation and phagocytosis assays in the presence of patient-derived amyloid extracts and synthetic amyloid fibrils as substrates and in the presence or absence of human serum.
RESULTS
Murine Igp5 exhibited highly potent binding to AL and ATTR amyloid extracts and diverse types of amyloid in formalin-fixed tissue sections. In the murine model of systemic AA amyloidosis, I-mIgp5 bound rapidly and specifically to amyloid deposits in all organs, including the heart, with no evidence of non-specific uptake in healthy tissues. The bioactivity of the immunoglobulin Fc domain was uncompromised in the context of mIgp5 and served as an effective opsonin. Macrophage-mediated uptake of amyloid extract and purified amyloid fibrils was enhanced by the addition of mIgp5. This effect was exaggerated in the presence of human serum coincident with deposition of complement C5b9.
CONCLUSION
Immunostimulatory, amyloid-clearing therapeutics can be developed by incorporating pan-amyloid-reactive peptides, such as p5, as a targeting moiety. The immunologic functionality of the IgG remains intact in the context of the fusion protein. These data highlight the potential use of peptide-antibody fusions as therapeutics for all types of systemic amyloidosis.
Topics: Mice; Animals; Humans; Disease Models, Animal; HEK293 Cells; Plaque, Amyloid; Amyloidosis; Amyloid; Amyloidogenic Proteins; Peptides; Immunoglobulin Light Chains
PubMed: 37854603
DOI: 10.3389/fimmu.2023.1275372 -
Colombia Medica (Cali, Colombia) 2023Amyloid light chain (AL) amyloidosis is characterized by amyloid fibril deposition derived from monoclonal immunoglobulin light chains, resulting in multiorgan...
BACKGROUND
Amyloid light chain (AL) amyloidosis is characterized by amyloid fibril deposition derived from monoclonal immunoglobulin light chains, resulting in multiorgan dysfunction. Limited data exist on the clinical features of AL amyloidosis.
OBJECTIVE
This study aims to describe the clinical characteristics, treatments, and outcomes in Colombian patients with AL amyloidosis.
METHODS
A retrospective descriptive study was conducted at three high-complexity centers in Medellín, Colombia. Adults with AL amyloidosis diagnosed between 2012 and 2022 were included. Clinical, laboratory, histological, treatment, and survival data were analyzed.
RESULTS
The study included 63 patients. Renal involvement was most prevalent (66%), followed by cardiac involvement (61%). Multiorgan involvement occurred in 61% of patients. Amyloid deposition was most commonly detected in renal biopsy (40%). Bortezomib-based therapy was used in 68%, and 23.8% received high-dose chemotherapy with autologous hematopoietic stem cell transplantation (HDCT-ASCT). Hematological response was observed in 95% of patients with available data. Cardiac and renal organ responses were 15% and 14%, respectively. Median overall survival was 45.1 months (95% CI: 22.2-63.8). In multivariate analysis, cardiac involvement was significantly associated with inferior overall survival (HR 3.27; 95% CI: 1.23-8.73; =0.018), HDCT-ASCT had a non-significant trend towards improved overall survival (HR 0.25; 95% CI: 0.06-1.09; =0.065).
CONCLUSIONS
In this study of Colombian patients with AL amyloidosis, renal involvement was more frequent than cardiac involvement. Overall survival and multiorgan involvement were consistent with data from other regions of the world. Multivariate analysis identified cardiac involvement and HDCT-AHCT as possible prognostic factors.
Topics: Adult; Humans; Immunoglobulin Light-chain Amyloidosis; Colombia; Retrospective Studies; Treatment Outcome; Bortezomib
PubMed: 38107838
DOI: 10.25100/cm.v54i3.5667 -
Chinese Medical Journal Jan 2024
Topics: Humans; Consensus; Immunoglobulin Light-chain Amyloidosis; Heart; Immunoglobulin Light Chains; China
PubMed: 38146261
DOI: 10.1097/CM9.0000000000002961 -
Cureus Aug 2023Systemic amyloid light chain, or primary amyloidosis (AL amyloidosis), is a serious medical condition that leads to the deposition of abnormal proteins called amyloid...
Systemic amyloid light chain, or primary amyloidosis (AL amyloidosis), is a serious medical condition that leads to the deposition of abnormal proteins called amyloid fibrils in various organs of the body. AL amyloidosis can present with different symptoms, which can make diagnosis challenging. This case report presents a clinical scenario of a 53-year-old female patient who had come in for shortness of breath and lower extremity swelling and was found to have acute on chronic pulmonary embolism. The patient had a history of systemic amyloidosis diagnosed with a kidney and duodenal biopsy. She also had a bone marrow biopsy done and was found to have IgG monoclonal gammopathy. Throughout the hospital course, patients required cautious diuretic use given the worsening kidney function. She was given intravenous anticoagulation initially and later switched to oral medication on discharge. Due to the aggressive nature of amyloidosis, a decision was made to start the patient on chemotherapy in an outpatient setting. This case presents an interesting scenario of systemic amyloidosis with concomitant monoclonal gammopathy that was complicated by acute pulmonary embolism. The case is important as it shows the different levels of amyloidosis and teaches us the benefit of taking a multidisciplinary approach to making a concrete plan for patients with advanced amyloidosis disease.
PubMed: 37727200
DOI: 10.7759/cureus.43753 -
ESC Heart Failure Jun 2024Predicting mortality in severe AL cardiac amyloidosis is challenging due to elevated biomarker levels and limited thresholds for stratifying severe cardiac damage. (Observational Study)
Observational Study
AIMS
Predicting mortality in severe AL cardiac amyloidosis is challenging due to elevated biomarker levels and limited thresholds for stratifying severe cardiac damage.
METHODS AND RESULTS
This prospective, observational, cohort study included de novo, confirmed cardiac AL amyloidosis patients at the Henri Mondor National Reference Centre. The goal was to identify predictors of mortality to enhance prognostic stratification and improve informed decision-making regarding therapy. Over the 12-year study period, among the 233 patients included, 133 were NYHA III-IV and 179 Mayo 2004 III. The independent predictors for mortality identified were hsTnT, NT-proBNP, cardiac output, and conjugated bilirubin. A novel prognostic, conditional stratification, Mondor amyloidosis cardiac staging (MACS) was developed with biomarker cut-off values for Stage 1: hsTnT ≤ 107 ng/L and NT-proBNP ≤ 3867 ng/L (n = 77; 33%); for stage 2 NT-proBNP > 3867 ng/L (n = 72; 30%). For stage 3, if troponin >107 ng/L, regardless of NT-proBNP then CB 4 μmol/L, was added (n = 41; 17.5%) and stage 4: CB > 4 μmol/L (n = 43; 18.5%). The median overall survival was 8 months 95% CI [2-24]. At 1 year, 102 (44%) patients died and the Kaplan-Meier median survival with MACS Stage 1 was not reached, while stage 2 was 15.2 months (95% CI [11-18]) and stage 3, 6.6 months (95% CI [1-13]). Notably, among European stage II patients, 17.1%, n = 8 were MACS stage 3 and European stage IIIb 21.4% (n = 23) were MACS stage 4. Importantly, among European stage IIIb patients 42.2% (n = 29) were classified MACS stage 4 and 12.5% n = 9 were only MACS stage 2.
CONCLUSIONS
The Mondor prognostic staging system, including conjugate bilirubin may significantly improve prognostic stratification for patients with severe cardiac amyloidosis.
Topics: Humans; Male; Female; Prospective Studies; Prognosis; Cardiomyopathies; Aged; Middle Aged; Biomarkers; Survival Rate; Immunoglobulin Light-chain Amyloidosis; Follow-Up Studies; Natriuretic Peptide, Brain; Peptide Fragments
PubMed: 38444090
DOI: 10.1002/ehf2.14671 -
International Journal of Cardiology May 2024Cardiac amyloidosis is increasingly recognized as a significant contributor to cardiovascular morbidity and mortality. With the emergence of novel therapies, there is a... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Cardiac amyloidosis is increasingly recognized as a significant contributor to cardiovascular morbidity and mortality. With the emergence of novel therapies, there is a growing interest in prognostication of patients with cardiac amyloidosis using cardiac magnetic resonance imaging (CMR). In this systematic review and meta-analysis, we aimed to examine the prognostic significance of myocardial native T1 and T2, and extracellular volume (ECV).
METHODS
Observational cohort studies or single arms of clinical trials were eligible. MEDLINE, EMBASE and CENTRAL were systematically searched from their respective dates of inception to January 2023. No exclusions were made based on date of publication, study outcomes, or study language. The study populations composed of adult patients (≥18 years old) with amyloid cardiomyopathy. All studies included the use of CMR with and without intravenous gadolinium contrast administration to assess myocardial native T1 mapping, T2 mapping, and ECV in association with the pre-specified primary outcome of all-cause mortality. Data were extracted from eligible primary studies by two independent reviewers and pooled via the inverse variance method using random effects models for meta-analysis.
RESULTS
A total of 3852 citations were reviewed. A final nine studies including a total of 955 patients (mean age 65 ± 10 years old, 32% female, mean left ventricular ejection fraction (LVEF) 59 ± 12% and 24% had NYHA class III or IV symptoms) with cardiac amyloidosis [light chain amyloidosis (AL) 50%, transthyretin amyloidosis (ATTR) 49%, other 1%] were eligible for inclusion and suitable for data extraction. All included studies were single centered (seven with 1.5 T MRI scanners, two with 3.0 T MRI scanners) and non-randomized in design, with follow-up spanning from 8 to 64 months (median follow-up = 25 months); 320 patients died during follow-up, rendering a weighted mortality rate of 33% across studies. Compared with patients with AL amyloid, patients with ATTR amyloid had significantly higher mean left ventricular mass index (LVMi) (102 ± 34 g/m vs 127 ± 37 g/m, p = 0.02). N-terminal pro-brain natriuretic peptide (NT-proBNP), troponin T levels, mean native T1 values, ECV and T2 values did not differ between patients with ATTR amyloid and AL amyloid (all p > 0.25). Overall, the hazard ratios for mortality were 1.33 (95% CI = [1.10, 1.60]; p = 0.003; I = 29%) for every 60 ms higher T1 time, 1.16 (95% CI = [1.09, 1.23], p < 0.0001; I = 76%) for every 3% higher ECV, and 5.23 (95% CI = [2.27, 12.02]; p < 0.0001; I = 0%) for myocardial-to-skeletal T2 ratio below the mean (vs above the mean).
CONCLUSION
Higher native T1 time and ECV, and lower myocardial to skeletal T2 ratio, on CMR are associated with worse mortality in patients with cardiac amyloidosis. Therefore, tissue mapping using CMR may offer a useful non-invasive technique to monitor disease progression and determine prognosis in patients with cardiac amyloidosis.
Topics: Adult; Humans; Female; Middle Aged; Aged; Adolescent; Male; Cardiomyopathies; Stroke Volume; Ventricular Function, Left; Magnetic Resonance Imaging; Myocardium; Amyloid Neuropathies, Familial; Disease Progression; Magnetic Resonance Imaging, Cine; Predictive Value of Tests; Contrast Media; Observational Studies as Topic
PubMed: 38382853
DOI: 10.1016/j.ijcard.2024.131892