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Annals of Internal Medicine Mar 2023Amyloidosis is a pathologic and clinical condition resulting from the accumulation of insoluble aggregates of misfolded proteins in tissues. Extracellular deposition of... (Review)
Review
Amyloidosis is a pathologic and clinical condition resulting from the accumulation of insoluble aggregates of misfolded proteins in tissues. Extracellular deposition of amyloid fibrils in the myocardium leads to cardiac amyloidosis, which is often overlooked as a cause of diastolic heart failure. Although cardiac amyloidosis was previously believed to have a poor prognosis, recent advances in diagnosis and treatment have emphasized the importance of early recognition and changed management of this condition. This article provides an overview of cardiac amyloidosis and summarizes current screening, diagnosis, evaluation, and treatment options.
Topics: Humans; Cardiomyopathies; Myocardium; Amyloidosis; Prognosis
PubMed: 36913688
DOI: 10.7326/AITC202303210 -
Journal of the American College of... Nov 2019The prevalence of calcific aortic stenosis (AS) and of cardiac amyloidosis (CA) increases with age, and their association is not uncommon in the elderly. The... (Review)
Review
The prevalence of calcific aortic stenosis (AS) and of cardiac amyloidosis (CA) increases with age, and their association is not uncommon in the elderly. The identification of CA is particularly challenging in patients with AS because these 2 conditions share several features. It is estimated that ≤15% of the AS population and ≤30% of the subset with low-flow, low-gradient pattern may have CA. In patients with AS, CA is associated with increased risk of heart failure, mortality, and treatment futility with aortic valve replacement. In case of suspicion of CA, it is thus crucial to confirm the diagnosis to guide therapeutic management of AS and eventually implement recently developed pharmacological treatment dedicated to transthyretin amyloidosis. Given the high surgical risk of patients with AS and concomitant CA, transcatheter aortic valve replacement may be preferred to surgery in these patients.
Topics: Amyloidosis; Aortic Valve; Aortic Valve Stenosis; Calcinosis; Humans; Prevalence
PubMed: 31753206
DOI: 10.1016/j.jacc.2019.09.056 -
Molecules (Basel, Switzerland) Feb 2022The amyloid hypothesis of Alzheimer's disease has long been the predominant theory, suggesting that Alzheimer's disease is caused by the accumulation of amyloid beta... (Review)
Review
The amyloid hypothesis of Alzheimer's disease has long been the predominant theory, suggesting that Alzheimer's disease is caused by the accumulation of amyloid beta protein (Aβ) in the brain, leading to neuronal toxicity in the central nervous system (CNS). Because of breakthroughs in molecular medicine, the amyloid pathway is thought to be central to the pathophysiology of Alzheimer's disease (AD). Currently, it is believed that altered biochemistry of the Aβ cycle remains a central biological feature of AD and is a promising target for treatment. This review provides an overview of the process of amyloid formation, explaining the transition from amyloid precursor protein to amyloid beta protein. Moreover, we also reveal the relationship between autophagy, cerebral blood flow, ACHE, expression of LRP1, and amyloidosis. In addition, we discuss the detailed pathogenesis of amyloidosis, including oxidative damage, tau protein, NFTs, and neuronal damage. Finally, we list some ways to treat AD in terms of decreasing the accumulation of Aβ in the brain.
Topics: Alzheimer Disease; Amyloid; Amyloid beta-Peptides; Amyloidosis; Animals; Autophagy; Biomarkers; Brain; Disease Management; Disease Susceptibility; Gene Expression Regulation; Humans; Plaque, Amyloid; Risk Factors
PubMed: 35209007
DOI: 10.3390/molecules27041210 -
Rheumatic Diseases Clinics of North... Nov 2018Secondary, AA, amyloidosis is a rare systemic complication that can develop in any long-term inflammatory disorder, and is characterized by the extracellular deposition... (Review)
Review
Secondary, AA, amyloidosis is a rare systemic complication that can develop in any long-term inflammatory disorder, and is characterized by the extracellular deposition of fibrils derived from serum amyloid A (SAA) protein. SAA is an acute-phase reactant synthetized largely by hepatocytes under the transcriptional regulation of proinflammatory cytokines. The kidney is the major involved organ with proteinuria as first clinical manifestation; renal biopsy is the commonest diagnostic investigation. Targeted anti-inflammatory treatment promotes normalization of circulating SAA levels preventing amyloid deposition and renal damage. Novel therapies aimed at promoting clearance of existing amyloid deposits soon may be an effective treatment approach.
Topics: Amyloidosis; Anti-Inflammatory Agents; Humans; Inflammation; Kidney; Serum Amyloid A Protein; Therapies, Investigational; Treatment Outcome
PubMed: 30274625
DOI: 10.1016/j.rdc.2018.06.004 -
Protoplasma Sep 2020Amyloidosis is a diverse group of protein conformational disorder which is caused by accumulation and deposition of insoluble protein fibrils in vital tissues or organs,... (Review)
Review
Amyloidosis is a diverse group of protein conformational disorder which is caused by accumulation and deposition of insoluble protein fibrils in vital tissues or organs, instigating organ dysfunction. Renal amyloidosis is characterized by the acellular Congo red-positive pathologic deposition of amyloid fibrils within glomeruli and/or the interstitium. It is generally composed of serum amyloid A-related protein or an immunoglobulin light chain; other rare forms lysozyme, gelsolin, fibrinogen alpha chain, transthyretin, apolipoproteins AI/AII/AIV/CII/CIII; and the recently identified form ALECT2. This disease typically manifests with heavy proteinuria, nephrotic syndrome, and finally progression to end-stage renal failure. Early diagnosis of renal amyloidosis is arduous as its symptoms appear in later stages with prominent amyloid deposition. The identification of the correct type of amyloidosis is quite troublesome as it can be confused with another related form. Therefore, the exact typing of amyloid is essential for prognosis, treatment, and correct management of renal amyloidosis. The emanation of new techniques of proteomic analysis, for instance, mass spectroscopy/laser microdissection, has provided greater accuracy in amyloid typing. This in-depth review emphasizes on the clinical features, renal pathological findings, and diagnosis of the AL and non-AL forms of renal amyloidosis.
Topics: Amyloidosis; Humans; Kidney; Prognosis
PubMed: 32447467
DOI: 10.1007/s00709-020-01513-0 -
Journal of Alzheimer's Disease : JAD 2019The amyloid hypothesis (AH) is still the most accepted model to explain the pathogenesis of inherited Alzheimer's disease (IAD). However, despite the neuropathological... (Review)
Review
The amyloid hypothesis (AH) is still the most accepted model to explain the pathogenesis of inherited Alzheimer's disease (IAD). However, despite the neuropathological overlapping with the non-inherited form (NIAD), AH waver in explaining NIAD. Thus, 30 years after its first statement several questions are still open, mainly regarding the role of amyloid plaques (AP) and apolipoprotein E (APOE). Accordingly, a pathogenetic model including the role of AP and APOE unifying IAD and NIAD pathogenesis is still missing. In the present understanding of the AH, we suggested that amyloid-β (Aβ) peptides production and AP formation is a physiological aging process resulting from a systemic age-related decrease in the efficiency of the proteins catabolism/clearance machinery. In this pathogenetic model Aβ peptides act as neurotoxic molecules, but only above a critical concentration [Aβ]c. A threshold mechanism triggers IAD/NIAD onset only when [Aβ]≥[Aβ]c. In this process, APOE modifies [Aβ]c threshold in an isoform-specific way. Consequently, all factors influencing Aβ anabolism, such as amyloid beta precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) gene mutations, and/or Aβ catabolism/clearance could contribute to exceed the threshold [Aβ]c, being characteristic of each individual. In this model, AP formation does not depend on [Aβ]c. The present interpretation of the AH, unifying the pathogenetic theories for IAD and NIAD, will explain why AP and APOE4 may be observed in healthy aging and why they are not the cause of AD. It is clear that further studies are needed to confirm our pathogenetic model. Nevertheless, our suggestion may be useful to better understand the pathogenesis of AD.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloidogenic Proteins; Amyloidosis; Animals; Apolipoproteins E; Humans; Metabolic Clearance Rate; Plaque, Amyloid
PubMed: 30883346
DOI: 10.3233/JAD-180802 -
Blood Cancer Journal May 2021Amyloid light chain (AL) amyloidosis is among the more common and more severe of the amyloidoses usually involving the slow proliferation of a bone-marrow-residing... (Review)
Review
Amyloid light chain (AL) amyloidosis is among the more common and more severe of the amyloidoses usually involving the slow proliferation of a bone-marrow-residing plasma cell (PC) clone and the secretion of unstable immunoglobulin-free light chains (FLC) that infiltrate peripheral tissues and result in detrimental end-organ damage. Disease presentation is rather vague, and the hallmark of treatment is early diagnosis before irreversible end-organ damage. Once diagnosed, treatment decision is transplant-driven whereby ~20% of patients are eligible for autologous stem cell transplantation (ASCT) with or without bortezomib-based induction. In the setting of ASCT-ineligibility, bortezomib plays a central role in upfront treatment with the recent addition of daratumumab to the current emerging standard of care. In general, management of AL amyloidosis is aimed at achieving deep, durable responses with very close monitoring for early detection of relapse/refractory disease. This article provides a comprehensive review of the management of patients with AL amyloidosis including goals of therapy, current treatment guidelines in the setting of both ASCT-eligibility and ineligibility, treatment response monitoring recommendations, toxicity management, and treatment of relapse/refractory disease.
Topics: Animals; Antineoplastic Agents; Bortezomib; Disease Management; Humans; Immunoglobulin Light-chain Amyloidosis; Neoplasm Recurrence, Local; Stem Cell Transplantation; Transplantation, Autologous
PubMed: 34006856
DOI: 10.1038/s41408-021-00486-4 -
ESC Heart Failure Dec 2019Transthyretin cardiac amyloidosis (ATTR-CA) demonstrates progressive, potentially fatal, and infiltrative cardiomyopathy caused by extracellular deposition of... (Review)
Review
Transthyretin cardiac amyloidosis (ATTR-CA) demonstrates progressive, potentially fatal, and infiltrative cardiomyopathy caused by extracellular deposition of transthyretin-derived insoluble amyloid fibrils in the myocardium. Two distinct types of transthyretin (wild type or variant) become unstable, and misfolding forms aggregate, resulting in amyloid fibrils. ATTR-CA, which has previously been underrecognized and considered to be rare, has been increasingly recognized as a cause of heart failure with preserved ejection fraction among elderly persons. With the advanced technology, the diagnostic tools have been improving for cardiac amyloidosis. Recently, the efficacy of several disease-modifying agents focusing on the amyloidogenic process has been demonstrated. ATTR-CA has been changing from incurable to treatable. Nevertheless, there are still no prognostic improvements due to diagnostic delay or misdiagnosis because of phenotypic heterogeneity and co-morbidities. Thus, it is crucial for clinicians to be aware of this clinical entity for early diagnosis and proper treatment. In this mini-review, we focus on recent advances in diagnosis and treatment of ATTR-CA.
Topics: Aged; Amyloid; Amyloidosis; Cardiomyopathies; Female; Heart; Heart Failure; Humans; Male; Middle Aged; Myocardium; Prealbumin
PubMed: 31553132
DOI: 10.1002/ehf2.12518 -
Annual Review of Biochemistry Jun 2017Peptides and proteins have been found to possess an inherent tendency to convert from their native functional states into intractable amyloid aggregates. This phenomenon... (Review)
Review
Peptides and proteins have been found to possess an inherent tendency to convert from their native functional states into intractable amyloid aggregates. This phenomenon is associated with a range of increasingly common human disorders, including Alzheimer and Parkinson diseases, type II diabetes, and a number of systemic amyloidoses. In this review, we describe this field of science with particular reference to the advances that have been made over the last decade in our understanding of its fundamental nature and consequences. We list the proteins that are known to be deposited as amyloid or other types of aggregates in human tissues and the disorders with which they are associated, as well as the proteins that exploit the amyloid motif to play specific functional roles in humans. In addition, we summarize the genetic factors that have provided insight into the mechanisms of disease onset. We describe recent advances in our knowledge of the structures of amyloid fibrils and their oligomeric precursors and of the mechanisms by which they are formed and proliferate to generate cellular dysfunction. We show evidence that a complex proteostasis network actively combats protein aggregation and that such an efficient system can fail in some circumstances and give rise to disease. Finally, we anticipate the development of novel therapeutic strategies with which to prevent or treat these highly debilitating and currently incurable conditions.
Topics: Alzheimer Disease; Amyloid; Amyloidosis; Diabetes Mellitus, Type 2; Drugs, Investigational; Gene Expression Regulation; History, 21st Century; Humans; Immunoglobulin Light-chain Amyloidosis; Molecular Chaperones; Molecular Targeted Therapy; Parkinson Disease; Protein Aggregation, Pathological; Protein Conformation; Protein Folding; Proteostasis Deficiencies
PubMed: 28498720
DOI: 10.1146/annurev-biochem-061516-045115 -
The Journal of Hand Surgery Oct 2019Carpal tunnel syndrome (CTS) can be caused by the deposition and accumulation of misfolded proteins called amyloid and is often an early manifestation of systemic... (Review)
Review
Carpal tunnel syndrome (CTS) can be caused by the deposition and accumulation of misfolded proteins called amyloid and is often an early manifestation of systemic amyloidosis. In patients undergoing surgery for idiopathic CTS, a recent study identified amyloidosis by tenosynovial biopsy in 10.2% of men older than 50 years and women older than 60 years; all positive patients had bilateral symptoms. These findings have led to a renewed interest in amyloidosis as an etiology of CTS. The 2 most common systemic amyloidoses, immunoglobulin light chain and transthyretin amyloidosis, affect the heart, nerves, and other organ systems throughout the body including the soft tissues. Patients with cardiac involvement of amyloidosis have an especially poor prognosis if the disease remains unrecognized and untreated. Early diagnosis is paramount, and patients classically present with cardiac disease several years after being operated on by a hand surgeon for carpal tunnel release. Herein, we present a review of amyloidosis as it pertains to CTS and an algorithm for the detection of amyloidosis in patients undergoing carpal tunnel release. Implementation of this straightforward algorithm will allow for early diagnosis of amyloidosis, a group of progressive and lethal diseases.
Topics: Algorithms; Amyloidosis; Biopsy; Carpal Tunnel Syndrome; Connective Tissue; Early Diagnosis; Humans; Plaque, Amyloid; Reoperation; Rupture; Synovial Membrane; Tendon Injuries; Tendons; Trigger Finger Disorder
PubMed: 31400950
DOI: 10.1016/j.jhsa.2019.06.016