-
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 -
Neurological Sciences : Official... Dec 2022Hereditary amyloidogenic transthyretin (ATTRv) amyloidosis is a rare autosomal dominantly inherited disorder caused by mutations in the transthyretin (TTR) gene. The... (Review)
Review
Hereditary amyloidogenic transthyretin (ATTRv) amyloidosis is a rare autosomal dominantly inherited disorder caused by mutations in the transthyretin (TTR) gene. The pathogenetic model of ATTRv amyloidosis indicates that amyloidogenic, usually missense, mutations destabilize the native TTR favouring the dissociation of the tetramer into partially unfolded species that self-assemble into amyloid fibrils. Amyloid deposits and monomer-oligomer toxicity are the basis of multisystemic ATTRv clinical involvement. Peripheral nervous system (autonomic and somatic) and heart are the most affected sites. In the last decades, a better knowledge of pathomechanisms underlying the disease led to develop novel and promising drugs that are rapidly changing the natural history of ATTRv amyloidosis. Thus, clinicians face the challenge of timely diagnosis for addressing patients to appropriate treatment. As well, the progressive nature of ATTRv raises the issue of presymptomatic testing and risk management of carriers. The main aim of this review was to focus on what we know about ATTRv so far, from pathogenesis to clinical manifestations, diagnosis and hence patient's monitoring and treatment, and from presymptomatic testing to management of carriers.
Topics: Humans; Amyloid Neuropathies, Familial; Genetic Testing; Mutation; Prealbumin
PubMed: 33188616
DOI: 10.1007/s10072-020-04889-2 -
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 -
Diabetologia Oct 2020For much of the last century, our knowledge regarding the pancreas in type 1 and type 2 diabetes was largely derived from autopsy studies of individuals with these... (Review)
Review
For much of the last century, our knowledge regarding the pancreas in type 1 and type 2 diabetes was largely derived from autopsy studies of individuals with these disorders or investigations utilising rodent models of either disease. While many important insights emanated from these efforts, the mode for investigation has increasingly seen change due to the availability of transplant-quality organ-donor tissues, improvements in pancreatic imaging, advances in metabolic assessments of living patients, genetic analyses, technological advances for laboratory investigation and more. As a result, many long-standing notions regarding the role for and the changes that occur in the pancreas in individuals with these disorders have come under question, while, at the same time, new issues (e.g., beta cell persistence, disease heterogeneity, exocrine contributions) have arisen. In this article, we will consider the vital role of the pancreas in human health and physiology, including discussion of its anatomical features and dual (exocrine and endocrine) functions. Specifically, we convey changes that occur in the pancreas of those with either type 1 or type 2 diabetes, with careful attention to the facets that may contribute to the pathogenesis of either disorder. Finally, we discuss the emerging unknowns with the belief that understanding the role of the pancreas in type 1 and type 2 diabetes will lead to improvements in disease diagnosis, understanding of disease heterogeneity and optimisation of treatments at a personalised level. Graphical abstract.
Topics: Adipose Tissue; Amyloidosis; Autoimmunity; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Glucagon-Secreting Cells; Humans; Insulin-Secreting Cells; Islet Amyloid Polypeptide; Islets of Langerhans; Pancreas; Pancreas, Exocrine; Somatostatin-Secreting Cells
PubMed: 32894306
DOI: 10.1007/s00125-020-05203-7 -
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 -
The Journal of Experimental Medicine Jan 2023Variants in the triggering receptor expressed on myeloid cells 2 (TREM2) gene are associated with increased risk for late-onset AD. Genetic loss of or decreased TREM2...
Variants in the triggering receptor expressed on myeloid cells 2 (TREM2) gene are associated with increased risk for late-onset AD. Genetic loss of or decreased TREM2 function impairs the microglial response to amyloid-β (Aβ) plaques, resulting in more diffuse Aβ plaques and increased peri-plaque neuritic dystrophy and AD-tau seeding. Thus, microglia and TREM2 are at a critical intersection of Aβ and tau pathologies in AD. Since genetically decreasing TREM2 function increases Aβ-induced tau seeding, we hypothesized that chronically increasing TREM2 signaling would decrease amyloid-induced tau-seeding and spreading. Using a mouse model of amyloidosis in which AD-tau is injected into the brain to induce Aβ-dependent tau seeding/spreading, we found that chronic administration of an activating TREM2 antibody increases peri-plaque microglial activation but surprisingly increases peri-plaque NP-tau pathology and neuritic dystrophy, without altering Aβ plaque burden. Our data suggest that sustained microglial activation through TREM2 that does not result in strong amyloid removal may exacerbate Aβ-induced tau pathology, which may have important clinical implications.
Topics: Alzheimer Disease; Amyloid; Amyloid beta-Peptides; Amyloidosis; Animals; Disease Models, Animal; Microglia; Plaque, Amyloid
PubMed: 36219197
DOI: 10.1084/jem.20220654 -
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 -
Brazilian Journal of Medical and... 2022Amyloidoses are a group of disorders in which soluble proteins aggregate and deposit extracellularly in tissues as insoluble fibrils, causing organ dysfunction. Clinical... (Review)
Review
Amyloidoses are a group of disorders in which soluble proteins aggregate and deposit extracellularly in tissues as insoluble fibrils, causing organ dysfunction. Clinical management depends on the subtype of the protein deposited and the affected organs. Systemic amyloidosis may stem from anomalous proteins, such as immunoglobulin light chains or serum amyloid proteins in chronic inflammation or may arise from hereditary disorders. Hereditary amyloidosis consists of a group of rare conditions that do not respond to chemotherapy, hence the identification of the amyloid subtype is essential for diagnosis, prognosis, and treatment. The kidney is the organ most frequently involved in systemic amyloidosis. Renal amyloidosis is characterized by acellular pathologic Congo red-positive deposition of amyloid fibrils in glomeruli, vessels, and/or interstitium. This disease manifests with heavy proteinuria, nephrotic syndrome, and progression to end-stage kidney failure. In some situations, it is not possible to identify the amyloid subtype using immunodetection methods, so the diagnosis remains indeterminate. In cases where hereditary amyloidosis is suspected or cannot be excluded, genetic testing should be considered. Of note, laser microdissection/mass spectrometry is currently the gold standard for accurate diagnosis of amyloidosis, especially in inconclusive cases. This article reviews the clinical manifestations and the current diagnostic landscape of renal amyloidosis.
Topics: Amyloid; Amyloidogenic Proteins; Amyloidosis; Amyloidosis, Familial; Congo Red; Humans; Immunoglobulin Light Chains
PubMed: 36197414
DOI: 10.1590/1414-431X2022e12284 -
Blood Oct 2021Although light-chain amyloidosis (AL) and multiple myeloma (MM) are characterized by tumor plasma cell (PC) expansion in bone marrow (BM), their clinical presentation...
Although light-chain amyloidosis (AL) and multiple myeloma (MM) are characterized by tumor plasma cell (PC) expansion in bone marrow (BM), their clinical presentation differs. Previous attempts to identify unique pathogenic mechanisms behind such differences were unsuccessful, and no studies have investigated the differentiation stage of tumor PCs in patients with AL and MM. We sought to define a transcriptional atlas of normal PC development in secondary lymphoid organs (SLOs), peripheral blood (PB), and BM for comparison with the transcriptional programs (TPs) of tumor PCs in AL, MM, and monoclonal gammopathy of undetermined significance (MGUS). Based on bulk and single-cell RNA sequencing, we observed 13 TPs during transition of normal PCs throughout SLOs, PB, and BM. We further noted the following: CD39 outperforms CD19 to discriminate newborn from long-lived BM-PCs; tumor PCs expressed the most advantageous TPs of normal PC differentiation; AL shares greater similarity to SLO-PCs whereas MM is transcriptionally closer to PB-PCs and newborn BM-PCs; patients with AL and MM enriched in immature TPs had inferior survival; and protein N-linked glycosylation-related TPs are upregulated in AL. Collectively, we provide a novel resource to understand normal PC development and the transcriptional reorganization of AL and other monoclonal gammopathies.
Topics: Adult; Humans; Immunoglobulin Light-chain Amyloidosis; Multiple Myeloma; Plasma Cells; Transcriptome; Tumor Cells, Cultured
PubMed: 34133718
DOI: 10.1182/blood.2020009754 -
Nature Medicine Jul 2022Plasma phosphorylated tau 181 (P-tau181) and 217 (P-tau217) are indicators of both amyloid and tau pathology in clinical settings, but their performance in heterogeneous...
Plasma phosphorylated tau 181 (P-tau181) and 217 (P-tau217) are indicators of both amyloid and tau pathology in clinical settings, but their performance in heterogeneous community-based populations is unclear. We examined P-tau181 and P-tau217 (n = 1,329, aged 30-98 years), in the population-based Mayo Clinic Study of Aging. Continuous, unadjusted plasma P-tau181 and P-tau217 predicted abnormal amyloid positron-emission tomography (PET) (area under the receiver operating characteristic curve (AUROC) = 0.81-0.86) and tau PET entorhinal cortex (AUROC > 0.80), but was less predictive of a tau PET temporal region of interest (AUROC < 0.70). Multiple comorbidities were associated with higher plasma P-tau181 and P-tau217 levels; the difference between participants with and without chronic kidney disease (CKD) was similar to the difference between participants with and without elevated brain amyloid. The exclusion of participants with CKD and other comorbidities affected the establishment of a normal reference range and cutpoints. Understanding the effect of comorbidities on P-tau181 and P-tau217 levels is important for their future interpretation in the context of clinical screening, diagnosis or prognosis at the population level.
Topics: Alzheimer Disease; Amyloid; Amyloid beta-Peptides; Amyloidosis; Biomarkers; Humans; Positron-Emission Tomography; Renal Insufficiency, Chronic; tau Proteins
PubMed: 35618838
DOI: 10.1038/s41591-022-01822-2