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Biomedicines
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Amyloidosis: Current Status on Diagnosis, Management and Therapeutic Strategies
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Amyloidosis: Current Status on Diagnosis, Management and Therapeutic Strategies

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cell Biology and Pathology".

Deadline for manuscript submissions: closed (20 March 2023) | Viewed by 15557

Special Issue Editors

Dr. Angela Romano

E-Mail Website
Guest Editor
1. UOC Neurologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
2. Dipartimento di Neuroscienze, Università Cattolica del Sacro Cuore, Rome, Italy
Interests: neuropathies; amyloidosis; neurophysiology; biomarkers; follow-up strategies
Dr. Giulia Bisogni

E-Mail Website
Guest Editor
Centro Clinico NeMO Adulti, Fondazione Serena Onlus-Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
Interests: neuropathies; amyloidosis; neurophysiology; biomarkers; follow-up strategies

Special Issue Information

Dear Colleagues,

Amyloidosis is a heterogeneous group of protein-misfolding diseases characterized by the extracellular deposition of insoluble amyloid fibrils in various organs and tissues, potentially leading to progressive and life-threatening organ failure. These diseases typically show huge variability in clinical outcome and course, depending on the involved precursor protein and on the nature and degree of organ impairment.

Amyloidosis can be localized or, more commonly, systemic, and both acquired or hereditary, with AL amyloidosis and hereditary transthyretin amyloidosis (ATTRv) representing the most common forms.

Treatment varies depending on the cause of fibril precursor production. Early diagnosis is fundamental for improving prognosis and management, preventing further organ damage. However, diagnosis can often be difficult and challenging, given the great phenotypic heterogeneity of these diseases.

In the last few years, the field of amyloidosis has seen increased interest, especially due to great advances in its management and treatment, particularly for hereditary forms.

Nowadays, the availability of new drugs potentially able to prevent or delay disease progression, especially if started in the early stages of the disease, has prompted the search for reliable biomarkers aimed both at improving early diagnosis and monitoring disease severity and progression.

The identification and validation of new biomarkers could also shed light on the possible pathogenic mechanisms of these diseases, leading to potential innovative therapeutic targets.

This Special Issue will focus on the state of the art of the diagnosis and management of amyloidosis, with particular emphasis on the assessment of innovative biomarkers for disease diagnosis and monitoring.

Original research articles and reviews are welcome. Articles presenting new strategies supported by experimental or preclinical data will also be considered.

We look forward to receiving your contributions.

Dr. Angela Romano
Dr. Giulia Bisogni
Guest Editors

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • amyloidosis
  • protein misfolding
  • TTR
  • light-chain amyloidosis
  • diagnosis improvement
  • biomarkers
  • therapeutic strategies

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Published Papers (7 papers)

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Research

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15 pages, 5291 KiB  
Article
Deep Learning to Classify AL versus ATTR Cardiac Amyloidosis MR Images
by Philippe Germain, Armine Vardazaryan, Aissam Labani, Nicolas Padoy, Catherine Roy and Soraya El Ghannudi
Biomedicines 2023, 11(1), 193; https://doi.org/10.3390/biomedicines11010193 - 12 Jan 2023
Cited by 3 | Viewed by 2228
Abstract
The aim of this work was to compare the classification of cardiac MR-images of AL versus ATTR amyloidosis by neural networks and by experienced human readers. Cine-MR images and late gadolinium enhancement (LGE) images of 120 patients were studied (70 AL and 50 [...] Read more.
The aim of this work was to compare the classification of cardiac MR-images of AL versus ATTR amyloidosis by neural networks and by experienced human readers. Cine-MR images and late gadolinium enhancement (LGE) images of 120 patients were studied (70 AL and 50 TTR). A VGG16 convolutional neural network (CNN) was trained with a 5-fold cross validation process, taking care to strictly distribute images of a given patient in either the training group or the test group. The analysis was performed at the patient level by averaging the predictions obtained for each image. The classification accuracy obtained between AL and ATTR amyloidosis was 0.750 for cine-CNN, 0.611 for Gado-CNN and between 0.617 and 0.675 for human readers. The corresponding AUC of the ROC curve was 0.839 for cine-CNN, 0.679 for gado-CNN (p < 0.004 vs. cine) and 0.714 for the best human reader (p < 0.007 vs. cine). Logistic regression with cine-CNN and gado-CNN, as well as analysis focused on the specific orientation plane, did not change the overall results. We conclude that cine-CNN leads to significantly better discrimination between AL and ATTR amyloidosis as compared to gado-CNN or human readers, but with lower performance than reported in studies where visual diagnosis is easy, and is currently suboptimal for clinical practice. Full article
(This article belongs to the Special Issue Amyloidosis: Current Status on Diagnosis, Management and Therapeutic Strategies)
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10 pages, 474 KiB  
Article
Patisiran Enhances Muscle Mass after Nine Months of Treatment in ATTRv Amyloidosis: A Study with Bioelectrical Impedance Analysis and Handgrip Strength
by Vincenzo Di Stefano, Ewan Thomas, Paolo Alonge, Valerio Giustino, Guglielmo Pillitteri, Ignazio Leale, Angelo Torrente, Antonia Pignolo, Davide Norata, Salvatore Iacono, Antonino Lupica, Antonio Palma, Giuseppe Battaglia and Filippo Brighina
Biomedicines 2023, 11(1), 62; https://doi.org/10.3390/biomedicines11010062 - 27 Dec 2022
Cited by 6 | Viewed by 2164
Abstract
Background and aims. Hereditary transthyretin amyloidosis with polyneuropathy (ATTRv) is caused by mutations in the TTR gene, leading to misfolded monomers that aggregate generating amyloid fibrils. The clinical phenotype is heterogeneous, characterized by a multisystemic disease affecting the sensorimotor, autonomic functions along with [...] Read more.
Background and aims. Hereditary transthyretin amyloidosis with polyneuropathy (ATTRv) is caused by mutations in the TTR gene, leading to misfolded monomers that aggregate generating amyloid fibrils. The clinical phenotype is heterogeneous, characterized by a multisystemic disease affecting the sensorimotor, autonomic functions along with other organs. Patisiran is a small interfering RNA acting as a TTR silencer approved for the treatment of ATTRv. Punctual and detailed instrumental biomarkers are on demand for ATTRv to measure the severity of the disease and monitor progression and response to treatment. Methods. Fifteen patients affected by ATTRv amyloidosis (66.4 ± 7.8 years, six males) were evaluated before the start of therapy with patisiran and after 9-months of follow-up. The clinical and instrumental evaluation included body weight and height; Coutinho stage; Neuropathy Impairment Score (NIS); Karnofsky performance status (KPS); Norfolk QOL Questionnaire; Six-minute walking test (6 MWT); nerve conduction studies; handgrip strength (HGS); and bioimpedance analysis (BIA). Results. Body composition significantly changed following the 9-months pharmacological treatment. In particular, the patients exhibited an increase in fat free mass, body cell mass, and body weight with a decrease in fat mass. A significant increase after 9 months of treatment was observed for the 6 MWT. Coutinho stage, KPS, NIS, NIS-W, nerve conduction studies, Norfolk, COMPASS-31 scale, and HGS remained unchanged. Conclusions. BIA might represent a useful tool to assess the effects of multiorgan damage in ATTRv and to monitor disease progression and response to treatments. More evidence is still needed for HGS. Patisiran stabilizes polyneuropathy and preserves motor strength by increasing muscle mass after 9 months of treatment. Full article
(This article belongs to the Special Issue Amyloidosis: Current Status on Diagnosis, Management and Therapeutic Strategies)
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10 pages, 869 KiB  
Article
Diagnostic Accuracy of Bone Scintigraphy for the Histopathological Diagnosis of Cardiac Transthyretin Amyloidosis—A Retrospective Austrian Multicenter Study
by Nicolas Verheyen, Maria Ungericht, Lisa Paar, Kathrin Danninger, Stefanie Schneiderbauer-Porod, Franz Duca, Bernhard Cherouny, Viktoria Hoeller, Klemens Ablasser, David Zach, Ewald Kolesnik, Daniel Kiblboeck, Matthias Frick, Diana Bonderman, Josef Dierneder, Christian Ebner, Thomas Weber and Gerhard Pölzl
Biomedicines 2022, 10(12), 3052; https://doi.org/10.3390/biomedicines10123052 - 28 Nov 2022
Cited by 1 | Viewed by 1580
Abstract
We aimed to ascertain the real-world diagnostic accuracy of bone scintigraphy in combination with free light chain (FLC) assessment for transthyretin (ATTR) cardiac amyloidosis (CA) using the histopathological diagnosis derived from endomyocardial biopsy (EMB) as a reference standard. We retrospectively analyzed 102 patients [...] Read more.
We aimed to ascertain the real-world diagnostic accuracy of bone scintigraphy in combination with free light chain (FLC) assessment for transthyretin (ATTR) cardiac amyloidosis (CA) using the histopathological diagnosis derived from endomyocardial biopsy (EMB) as a reference standard. We retrospectively analyzed 102 patients (22% women) with suspected CA from seven Austrian amyloidosis referral centers. The inclusion criteria comprised the available results of bone scintigraphy, FLC assessment, and EMB with histopathological analysis. ATTR and AL were diagnosed in 60 and 21 patients (59%, 21%), respectively, and concomitant AL and ATTR was identified in one patient. The specificity and positive predictive value (PPV) of Perugini score ≥ 2 for ATTR CA were 95% and 96%. AL was diagnosed in three out of 31 patients (10%) who had evidence of monoclonal proteins and a Perugini score ≥ 2. When excluding all patients with detectable monoclonal proteins (n = 62) from analyses, the PPV of Perugini score ≥ 2 for ATTR CA was 100% and the NPV of Perugini score < 2 for ATTR CA was 79%. Conclusively, ATTR CA can be diagnosed non-invasively in the case of a Perugini score ≥ 2 and an unremarkable FLC assessment. However, tissue biopsy is mandatory in suspected CA in any other constellation of non-invasive diagnostic work-up. Full article
(This article belongs to the Special Issue Amyloidosis: Current Status on Diagnosis, Management and Therapeutic Strategies)
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8 pages, 776 KiB  
Article
Quantitative Sensory Testing in Late-Onset ATTRv Presymptomatic Subjects: A Single Center Experience
by Stefano Tozza, Daniele Severi, Giovanni Palumbo, Vincenzo Provitera, Lucia Ruggiero, Raffaele Dubbioso, Rosa Iodice, Maria Nolano and Fiore Manganelli
Biomedicines 2022, 10(11), 2877; https://doi.org/10.3390/biomedicines10112877 - 10 Nov 2022
Cited by 6 | Viewed by 1432
Abstract
Backgrounds Hereditary transthyretin amyloidosis (ATTRv) presymptomatic subjects undergo multidisciplinary evaluation to detect, as early as possible, a subclinical involvement of multisystem disease. Quantitative sensory testing (QST) that investigates and discriminates the function of C, Aδ and Aβ fibers is included as an instrumental [...] Read more.
Backgrounds Hereditary transthyretin amyloidosis (ATTRv) presymptomatic subjects undergo multidisciplinary evaluation to detect, as early as possible, a subclinical involvement of multisystem disease. Quantitative sensory testing (QST) that investigates and discriminates the function of C, Aδ and Aβ fibers is included as an instrumental test to monitor nerve fiber function. The purpose of this study was to evaluate the role of QST in the context of the multidisciplinary evaluation in late onset carriers. Methods Four-teen presymptomatic (namely carriers) were enrolled. Subjects underwent thermal [cold and warm detection threshold (CDT, WDT), cold and heat pain (CP and HP)] and tactile QST in four body sites: foot dorsum, distal lateral leg, distal thigh, hand dorsum. Results Overall, presymptomatic subject showed a significant difference in all thermal QST findings compared to the control group. All subjects had at least one altered thermal QST finding; the sites more frequently altered were foot and leg, whilst the thermal modalities which were more frequently abnormal were CDT, WDT and CP. Conclusions Our study highlights the importance of performing thermal QST in subjects carrying TTR mutation, given the high frequency of abnormal findings. Notably, performing both innocuous and painful stimulation in foot and/or leg increases the chance of detecting nerve fiber dysfunction. Moreover, the investigation of the hand may provide useful information in monitoring disease progression before the Predicted Age of Disease Onset (PADO). Full article
(This article belongs to the Special Issue Amyloidosis: Current Status on Diagnosis, Management and Therapeutic Strategies)
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9 pages, 652 KiB  
Article
The Silent Period for Small Fiber Sensory Neuropathy Assessment in a Mixed Cohort of Transthyretin-Mediated Amyloidosis
by Chiara Cambieri, Laura Libonati, Federica Moret, Giorgio Tartaglia, Matteo Garibaldi, Cristina Chimenti, Maurizio Inghilleri and Marco Ceccanti
Biomedicines 2022, 10(9), 2073; https://doi.org/10.3390/biomedicines10092073 - 24 Aug 2022
Cited by 4 | Viewed by 1697
Abstract
Background: Transthyretin-mediated amyloidosis (ATTR) is a rare multisystemic disease involving the peripheral nervous system and heart. Autonomic and small fiber involvement is one of the hallmarks of ATTR, and many tools have been proposed to assess this aspect. Aim: The aim of this [...] Read more.
Background: Transthyretin-mediated amyloidosis (ATTR) is a rare multisystemic disease involving the peripheral nervous system and heart. Autonomic and small fiber involvement is one of the hallmarks of ATTR, and many tools have been proposed to assess this aspect. Aim: The aim of this study was to investigate cutaneous and mixed nerve silent periods (CSP and MnSP) as instruments for small fiber assessment. Methods: A total of 21 ATTR patients, 20 healthy controls, and 18 asymptomatic carriers underwent a sensory conduction study from the right sural and non-dominant ulnar nerves. A motor conduction study from the right deep peroneal and non-dominant ulnar nerves, with their F waves, CSPs, and MnSPs, was performed. Results: The amplitudes of the sural and ulnar sensory nerves and of the peroneal and ulnar motor nerves were reduced in ATTR patients compared to the other groups. F waves from the ulnar and peroneal nerves showed no differences between the three groups. The CSP and MnSP latency, but not amplitude, were increased in both the ulnar and peroneal nerves of ATTR patients. Conclusions: ATTR patients showed axonal involvement of large sensory and motor nerve fibers and demyelinating features of small sensory fibers. Full article
(This article belongs to the Special Issue Amyloidosis: Current Status on Diagnosis, Management and Therapeutic Strategies)
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Review

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13 pages, 1296 KiB  
Review
State of the Art of Cardiac Amyloidosis
by Nabil Belfeki, Nouha Ghriss, Mehran Monchi and Cyrus Moini
Biomedicines 2023, 11(4), 1045; https://doi.org/10.3390/biomedicines11041045 - 28 Mar 2023
Cited by 2 | Viewed by 2818
Abstract
Cardiac amyloidosis is defined by extracellular deposition of misfolded proteins in the heart. The most frequent cases of cardiac amyloidosis are caused by transthyretin and light chain amyloidosis. This condition is underdiagnosed, and its incidence has been continuously rising in recent studies because [...] Read more.
Cardiac amyloidosis is defined by extracellular deposition of misfolded proteins in the heart. The most frequent cases of cardiac amyloidosis are caused by transthyretin and light chain amyloidosis. This condition is underdiagnosed, and its incidence has been continuously rising in recent studies because of the aging of the population and the development of noninvasive multimodal diagnostic tools. Amyloid infiltration affects all cardiac tunics and causes heart failure with preserved ejection fraction, aortic stenosis, arrythmia, and conductive disorder. Innovative, specific therapeutic approaches have demonstrated an improvement in affected organs and the global survival of patients. This condition is no longer considered rare and incurable. Thus, better knowledge of the disease is mandatory. This review will provide a digest of the clinical signs and symptoms of cardiac amyloidosis, the diagnostic tools used to confirm the diagnosis, and current symptomatic and etiopathogenic management considerations according to guidelines and recommendations. Full article
(This article belongs to the Special Issue Amyloidosis: Current Status on Diagnosis, Management and Therapeutic Strategies)
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13 pages, 2604 KiB  
Review
Transthyretin Cardiac Amyloidosis: A Cardio-Orthopedic Disease
by Federico Perfetto, Mattia Zampieri, Giulia Bandini, Roberto Fedi, Roberto Tarquini, Raffaella Santi, Luca Novelli, Marco Allinovi, Alessia Argirò and Francesco Cappelli
Biomedicines 2022, 10(12), 3226; https://doi.org/10.3390/biomedicines10123226 - 12 Dec 2022
Cited by 4 | Viewed by 2757
Abstract
Orthopaedic manifestations of wild-type transthyretin amyloidosis are frequent and characteristic, including idiopathic bilateral carpal tunnel syndrome, idiopathic lumbar canal stenosis, atraumatic rupture of the brachial biceps tendon, and, more rarely, finger disease and rotator cuff. These manifestations often coexisting in the same patient, [...] Read more.
Orthopaedic manifestations of wild-type transthyretin amyloidosis are frequent and characteristic, including idiopathic bilateral carpal tunnel syndrome, idiopathic lumbar canal stenosis, atraumatic rupture of the brachial biceps tendon, and, more rarely, finger disease and rotator cuff. These manifestations often coexisting in the same patient, frequently male and aged, steadily precede cardiac involvement inducing a rapidly progressive heart failure with preserved ejection fraction. Although transthyretin cardiac amyloidosis remains a cardiac relevant disease, these extracardiac localisation may increase diagnostic suspicion and allow for early diagnosis assuming the role of useful diagnostic red flags, especially in light of new therapeutic opportunities that can slow or stop the progression of the disease. For the cardiologist, the recognition of these extracardiac red flags is of considerable importance to reinforce an otherwise less emerging diagnostic suspicion. For orthopedists and rheumatologists, the presence in an old patient with or without clinical manifestations of cardiovascular disease, of an unexpected and inexplicable constellation of musculoskeletal symptoms, can represent a fundamental moment for an early diagnosis and treatment is improving a patient’s outcome. Full article
(This article belongs to the Special Issue Amyloidosis: Current Status on Diagnosis, Management and Therapeutic Strategies)
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