Modeling transthyretin (TTR) amyloid diseases, from monomer to amyloid fibrils.

ATTR amyloidosis is caused by deposition of large, insoluble aggregates (amyloid fibrils) of cross-ß-sheet TTR protein molecules on the intercellular surfaces of tissues. The process of amyloid formation from monomeric TTR protein molecules to amyloid deposits has not been fully characterized and is therefore modeled in this paper. Two models are considered: 1) TTR monomers in the blood spontaneously fold into a ß-sheet conformation, aggregate into short proto-fibrils that then circulate in the blood until they find a complementary tissue where the proto-fibrils accumulate to form the large, insoluble amyloid fibrils found in affected tissues. 2) TTR monomers in the native or ß-sheet conformation circulate in the blood until they find a tissue binding site and deposit in the tissue or tissues forming amyloid deposits in situ. These models only differ on where the selection for ß-sheet complementarity occurs, in the blood where wt-wt, wt-v, and v-v interactions determine selectivity, or on the tissue surface where tissue-wt and tissure-v interactions also determine selectivity. Statistical modeling in both cases thus involves selectivity in fibril aggregation and tissue binding. Because binding of protein molecules into fibrils and binding of fibrils to tissues occurs through multiple weak non-covalent bonds, strong complementarity between ß-sheet molecules and between fibrils and tissues is required to explain the insolubility and tissue selectivity of ATTR amyloidosis. Observation of differing tissue selectivity and thence disease phenotypes from either pure wildtype TTR protein or a mix of wildtype and variant molecules in amyloid fibrils evidences the requirement for fibril-tissue complementarity. Understanding the process that forms fibrils and binds fibrils to tissues may lead to new possibilities for interrupting the process and preventing or curing ATTR amyloidosis.

Clinical Use of Biomarkers in Cardiac Amyloidosis.

Amyloidosis is a systemic condition characterized by multiple organs involvement. A multidisciplinary and multimodal approach in assessing patients is pivotal and recommended by the international scientific societies. Biomarkers represent an essential noninvasive tool to increase the suspicion of disease and orient further workup and clinical management of patients. This review provides an updated contemporary focus on the clinical use of biomarkers in cardiac amyloidosis, emphasizing their role in both the diagnostic and prognostic setting and discussing future perspective of emerging biomarkers.

Amyloidosis and Amyloidogenesis: One Name, Many Diseases.

Amyloidosis is a heterogenous group of disorders, caused by the deposition of insoluble fibrils derived from misfolded proteins in the extracellular space of various organs. These proteins have an unstable structure that causes them to misfold, aggregate, and deposit as amyloid fibrils with the pathognomonic histologic property of green birefringence when viewed under cross-polarized light after staining with Congo red. Amyloid fibrils are insoluble and degradation-resistant; resistance to catabolism results in progressive tissue amyloid accumulation. The outcome of this process is organ disfunction independently from the type of deposited protein, however there can be organ that are specifically targeted from certain proteins.

The Role of Scintigraphy with Bone Radiotracers in Cardiac Amyloidosis.

Cardiac amyloidosis (CA) is caused by the myocardial deposition of misfolded proteins, either amyloid transthyretin (ATTR) or immunoglobulin light chains (AL). The paradigm of this condition has transformed, since CA is increasingly recognized as a relatively prevalent cause of heart failure. Cardiac scintigraphy with bone tracers is the unique noninvasive technique able to confirm CA without performing tissue biopsy or advanced imaging tests. A moderate-to-intense myocardial uptake (Perugini grade ≥2) associated with the absence of a monoclonal component is greater than 99% specific for ATTR-CA, while AL-CA confirmation requires tissue biopsy.

Standard Therapy in Cardiac Amyloidosis: What is Known, What is "Gray".

Amyloidosis is a systemic disease due to the accumulation of misfolded amyloid fibrils that damage the heart and worsen the prognosis. Heart failure (HF), a condition frequently linked with an advanced stage of this disease, is the most prevalent clinical manifestation that leads to its diagnosis. However, due to the growing awareness of the occurrence of cardiac amyloidosis (CA), it is now possible to perform an early diagnosis and have a positive impact on its natural course. This study aims to highlight the most compelling issues concerning patients' clinical management with HF and CA.

Pathophysiology of Cardiac Amyloidosis.

Amyloidosis refers to a heterogeneous group of disorders sharing common pathophysiological mechanisms characterized by the extracellular accumulation of fibrillar deposits consisting of the aggregation of misfolded proteins. Cardiac amyloidosis (CA), usually caused by deposition of misfolded transthyretin or immunoglobulin light chains, is an increasingly recognized cause of heart failure burdened by a poor prognosis. CA manifests with a restrictive cardiomyopathy which progressively leads to biventricular thickening, diastolic and then systolic dysfunction, arrhythmias, and valvular disease. The pathophysiology of CA is multifactorial and includes increased oxidative stress, mitochondrial damage, apoptosis, impaired metabolism, and modifications of intracellular calcium balance.

The Role of Echocardiography for the Clinical Diagnosis, Risk Stratification, and Management of Cardiac Amyloidosis.

Amyloidosis is a rare, heterogeneous group of diseases characterized by extracellular infiltration and deposition of misfolded fibrils in different organs and tissues. A timely diagnosis is important as it can improve outcome. Echocardiography has emerged as a powerful tool to prompt suspicion and refer patients to second-level evaluation to reach a definitive diagnosis. In this scenario, new echo techniques offer new insight into the cardiac amyloidosis (CA) pathophysiology and clinical course. The present review aims to describe the developments in echocardiographic assessment of patients with suspected CA and it summarizes new available echocardiographic scores able to guide a definite diagnosis.

Cardiovascular Magnetic Resonance in the Management of Cardiac Amyloidosis: Current and Future Clinical Applications.

Cardiac magnetic resonance represents the gold standard imaging technique to assess cardiac volumes, wall thickness, mass, and systolic function but also to provide noninvasive myocardial tissue characterization across almost all cardiac diseases. In patients with cardiac amyloidosis, increased wall thickness of all heart chambers, a mildly reduced ejection fraction and occasionally pleural and pericardial effusion are the characteristic morphologic anomalies. The typical pattern after contrast injection is represented by diffuse areas of late gadolinium enhancement, which can be focal and patchy in very early stages, circumferential, and subendocardial in intermediate stages or even diffuse transmural in more advanced stages.

The Most Predictive Red Flags for Suspecting Cardiac Amyloidosis in Patients with Heart Failure with Preserved Ejection Fraction.

OBJECTIVE: Cardiac amyloidosis (CA) is a cardiomyopathy characterized by amyloid infiltration in the myocardium. Transthyretin cardiac amyloidosis (TTR-CA), commonly presenting as heart failure with preserved ejection fraction (HFpEF), was the focus of our study, which aimed to identify red flags that heighten suspicion of CA in HFpEF patients. METHODS: We prospectively included patients diagnosed with HFpEF. All patients were assessed for TTR-CA red flag features, cardiac and extra-cardiac, as outlined in the 'Diagnosis and Treatment of Cardiac Amyloidosis: A Position Statement of the European Society of Cardiology.' Technetium-99m pyrophosphate (99mTc-PYP) cardiac scintigraphy was performed in 167 HFpEF patients suspected of having TTR-CA. Patients testing positive and negative for TTR-CA were compared based on these red flag features. RESULTS: Out of 167 HFpEF patients, 19 (11.3%) were diagnosed with TTR-CA. In the TTR-CA group, 17 (89.5%) patients were 65 years or older. The presence of three or more red flags differentiated the TTR-CA positive and negative groups (P = 0.040). Features such as low voltage and pseudo infarct patterns were more prevalent in the TTR-CA group (P < 0.001 and P < 0.048, respectively). Left ventricular global longitudinal strain (LV-GLS) was lower in the TTR-CA positive group (P < 0.001). Multivariate analysis identified four variables-older age, pseudo infarct pattern, low/decreased QRS voltage, and LV-GLS-as strong, independent predictors of TTR-CA, with significant odds ratios (ORs) of 7.8, 6.8, 16.9, and 1.2, respectively. CONCLUSION: In this study, TTR-CA etiology occurs in approximately one in every ten HFpEF patients. The presence of three or more red flags increases the likelihood of TTR-CA. Older age, pseudo infarct pattern, low/decreased QRS voltage, and reduced LV-GLS are the most significant red flags indicating TTR-CA in HFpEF patients.

Alzheimer-Type Cerebral Amyloidosis in the Context of HIV Infection: Implications for a Proposed New Treatment Approach.

Reverse transcriptase inhibitors (RTIs) are currently broadly prescribed for the treatment of HIV infection but are also thought to prevent Alzheimer's disease (AD) progression by protecting against amyloidosis. Our study evaluates the hypothesis that reverse transcriptase inhibitors protect against Alzheimer-type brain amyloidogenesis in the context of HIV infection. We compiled a case series of participants from a prospective study of the neurological consequences of HIV infection at the HIV Neurobehavioral Research Program (HNRP) who had serial neuropsychological and neurological assessments and were on RTIs. Two participants had gross and microscopic examination and immunohistochemistry of the brain at autopsy; one was assessed clinically for Alzheimer's disease by cerebrospinal fluid (CSF) analysis of phosphorylated-Tau, Total-Tau and Aß42. Additionally, a larger cohort of 250 autopsied individuals was evaluated for presence of amyloid plaques, Tau, and related pathologies. Three older, virally suppressed individuals with HIV who had long-term treatment with RTIs were included in analyses. Two cases demonstrated substantial cerebral amyloid deposition at autopsy. The third case met clinical criteria for AD based on a typical clinical course and CSF biomarker profile. In the larger cohort of autopsied individuals, the prevalence of cerebral amyloidosis among people with HIV (PWH) was greater for those on RTIs. Our study showed that long-term RTI therapy did not protect against Alzheimer-type brain amyloidogenesis in the context of HIV infection in these patients. Given the known toxicities of RTIs, it is premature to recommend them to individuals at risk or with Alzheimer's disease who do not have HIV infection.

Effects of SPI1-mediated transcriptome remodeling on Alzheimer's disease-related phenotypes in mouse models of Aß amyloidosis.

SPI1 was recently reported as a genetic risk factor for Alzheimer's disease (AD) in large-scale genome-wide association studies. However, it is unknown whether SPI1 should be downregulated or increased to have therapeutic benefits. To investigate the effect of modulating SPI1 levels on AD pathogenesis, we performed extensive biochemical, histological, and transcriptomic analyses using both Spi1-knockdown and Spi1-overexpression mouse models. Here, we show that the knockdown of Spi1 expression significantly exacerbates insoluble amyloid-ß (Aß) levels, amyloid plaque deposition, and gliosis. Conversely, overexpression of Spi1 significantly ameliorates these phenotypes and dystrophic neurites. Further mechanistic studies using targeted and single-cell transcriptomics approaches demonstrate that altered Spi1 expression modulates several pathways, such as immune response pathways and complement system. Our data suggest that transcriptional reprogramming by targeting transcription factors, like Spi1, might hold promise as a therapeutic strategy. This approach could potentially expand the current landscape of druggable targets for AD.

[AL Amyloidosis].

AL amyloidosis, derived from amyloidogenic immunoglobulin light chains, is a common type of systemic amyloidosis. Peripheral neuropathy has been identified in 10%-40% of patients with systemic AL amyloidosis. Definitive diagnosis requires tissue biopsies, including skin, fat, and gastrointestinal samples, as well as amyloid typing. Disease-modifying therapies have been shown to improve patient survival and prevent progressive organ dysfunction.

Western diet increases brain metabolism and adaptive immune responses in a mouse model of amyloidosis.

Diet-induced increase in body weight is a growing health concern worldwide. Often accompanied by a low-grade metabolic inflammation that changes systemic functions, diet-induced alterations may contribute to neurodegenerative disorder progression as well. This study aims to non-invasively investigate diet-induced metabolic and inflammatory effects in the brain of an APPPS1 mouse model of Alzheimer's disease. [18F]FDG, [18F]FTHA, and [18F]GE-180 were used for in vivo PET imaging in wild-type and APPPS1 mice. Ex vivo flow cytometry and histology in brains complemented the in vivo findings. 1H- magnetic resonance spectroscopy in the liver, plasma metabolomics and flow cytometry of the white adipose tissue were used to confirm metaflammatory condition in the periphery. We found disrupted glucose and fatty acid metabolism after Western diet consumption, with only small regional changes in glial-dependent neuroinflammation in the brains of APPPS1 mice. Further ex vivo investigations revealed cytotoxic T cell involvement in the brains of Western diet-fed mice and a disrupted plasma metabolome. 1H-magentic resonance spectroscopy and immunological results revealed diet-dependent inflammatory-like misbalance in livers and fatty tissue. Our multimodal imaging study highlights the role of the brain-liver-fat axis and the adaptive immune system in the disruption of brain homeostasis in amyloid models of Alzheimer's disease.

Single German centre experience with patient journey and care-relevant needs in amyloidosis: The German AMY-NEEDS research and care program.

BACKGROUND: Amyloidosis is a rare multi-system disorder associated with frequently delayed diagnosis, enormous disease burden and psychosocial distress. METHODS: Systematic assessment of needs was performed by a subtype-spanning questionnaire-based survey within the AMY-NEEDS research and care program. RESULTS: 118 patients with proven amyloidosis (62.7% ATTR, 22.0% AL, 15.3% other forms) were included in August 2020 until February 2021 (mean age 71.2 ±11.3 years; 30% women). The median diagnostic delay between onset of symptoms and diagnosis was 9.0 (range: 2.5; 33.0) months. Local health care providers (HCPs) play a central role on the way to diagnosis. Diagnosis itself typically requires a clinical but not necessarily a university setting. In the treatment phase, the focus moves to the amyloidosis centre as primary contact and coordinator, with general practitioners (GPs) acting predominantly as a contact point in crisis and link to additional services. About half of patients reported impaired quality of life and one third suffering from anxiety and depressed mood, respectively. The majority of patients talk about their concerns with close caregivers and local HCPs. Advance care planning is a relevant, yet insufficiently met need. CONCLUSION: The journey of patients with amyloidotic disease, their contact partners and needs at different stages were characterized in detail within the German health care system. An amyloidosis-specific care concept has to master the multitude of interfaces connecting the numerous treatment providers involved with the amyloidosis centre and GPs as key players. Telemedical approaches could be a promising and well-accepted option allowing optimal coordination and communication.

[Bilateral vestibulopathy and sensorineural hearing loss in necrobiotic xanthogranuloma, multiple myeloma and amiloidosis]. / Dvustoronnyaya vestibulopatiya i sensonevral'naya tugoukhost' u patsienta s nekroticheskoi ksantogranulemoi, mnozhestvennoi mielomoi i amiloidozom.

This article describes a rare case of necrotic xanthogranuloma in a 46-year-old patient who presented with the development of periorbital xanthelasms, progressive bilateral sensorineural hearing loss and bilateral vestibulopathy, followed by multiple myeloma and amyloidosis. For several years, the patient underwent standard rehabilitation for chronic sensorineural hearing loss and was fitted with a hearing aid. During hospitalisation for exacerbation of chronic bronchitis, monoclonal gammopathy was identified, and later, after careful examination and repeated biopsies, necrotic xanthogranuloma, multiple myeloma and AL-amyloidosis were confirmed. Targeted immunochemotherapy resulted in improvement of hearing and significant recovery of the vestibuloocular reflex bilaterally.