Amyloid Deposits In Tissues Research Articles

Prevalence and predictors of neurological manifestations in systemic AL amyloidosis

IntroductionImmunoglobulin light chain (AL) amyloidosis is a life-threatening systemic disease due to plasma cell dyscrasias, which is characterized by amyloid deposition in various tissues. Neurological manifestations, in particular peripheral nervous system involvement, play a major role for quality of life and treatment decisions as frequently potentially neurotoxic drugs are used. MethodsWe retrospectively investigated the prevalence of neurological manifestations, its risk factors and prognostic value in 155 consecutive patients with AL amyloidosis in a single German tertiary center between 2010 and 2021. Multiple logistic regression was performed to identify predictors of amyloid neuropathy and the impact of peripheral neuropathy on patient survival was assessed by Cox proportional hazard regression analysis. ResultsNearly half of patients showed at least one of four neurological manifestations of AL amyloidosis which were frequent in our study: peripheral neuropathy (36.8%), carpal tunnel syndrome (12.9%), lumbar spinal stenosis (7.1%), and amyloid myopathy (3.9%). Male sex (OR 2.943, CI 1.152–8.139, p = 0.029) and cardiac involvement (OR 6.186, CI 1.449–43.38, p = 0.028) were independent predictors of peripheral neuropathy which was closely related to autonomic dysfunction in patients with AL amyloidosis. Peripheral neuropathy had no impact on survival (HR 0.952, CI 0.517–1.754, p = 0.876). ConclusionsNeurological involvement is common in systemic AL amyloidosis. Treatment decisions should take into account peripheral neuropathy, in particular in male patients with amyloid cardiomyopathy, but also amyloid myopathy that seems to be not as rare as previously suggested.

Complement in autoimmune inflammatory myopathies, the role of myositis-associated antibodies, COVID-19 associations and muscle amyloid deposits

Introduction The inflammatory myopathies (IM) have now evolved into distinct subsets requiring clarification about their immunopathogenesis to guide applications of targeted therapies Areas covered Immunohistopathologic criteria of IM with focus on complement, anti-complement therapeutics and other biologic immunotherapies. The COVID19-triggered muscle autoimmunity along with the correct interpretation of muscle amyloid deposits are discussed. Expert opinion The IM, unjustifiably referred as idiopathic, comprise Dermatomyositis (DM), Necrotizing Autoimmune Myositis (NAM), Anti-synthetase syndrome-overlap myositis (Anti-SS-OM), and Inclusion-Body-Myositis (IBM). In DM, complement activation with MAC-mediated endomysial microvascular destruction and perifascicular atrophy is the fundamental process, while innate immunity activation factors, INF1 and MxA, sense and secondarily enhance inflammation. Complement participates in muscle fiber necrosis from any cause and may facilitate muscle-fiber necrosis in NAM but seems unlikely that myositis-associated antibodies participate in complement-fixing. Accordingly, anti-complement therapeutics should be prioritized for DM. SARS-CoV-2 can potentially trigger muscle autoimmunity but systematic studies are needed as the reported autopsy findings are not clinically relevant. In IBM, tiny amyloid deposits within muscle fibers are enhanced by inflammatory mediators contributing to myodegeneration; in contrast, spotty amyloid deposits in the endomysial connective tissue do not represent “amyloid myopathy” but only have diagnostic value for amyloidosis due to any cause.

Inflammasome assembly is required for intracellular formation of β2-microglobulin amyloid fibrils, leading to IL-1β secretion.

IntroductionDialysis-related amyloidosis (DRA) caused by β2-microgloblin (B2M) fibrils is a serious complication for patients with kidney failure on long-term dialysis. Deposition of B2M amyloid fibrils is thought to be due not only to serum extracellular B2M but also to infiltrating inflammatory cells, which may have an important role in B2M amyloid deposition in osteoarticular tissues in patients with DRA. Here, we asked whether B2M amyloid fibrils activate the inflammasome and contribute to formation and deposition of amyloid fibrils in cells.MethodsAmyloid formation was confirmed by a thioflavin T (ThT) spectroscopic assay and scanning electron microscopy (SEM). Activation of inflammasomes was assessed by detecting interleukin (IL)-1β in culture supernatants from human embryonic kidney (HEK) 293T cells ectopically expressing inflammasome components. IL-1β secretion was measured by enzyme-linked immunosorbent assay. Expression and co-localization were analyzed by immunohistochemistry and dual immunofluorescence microscopy.ResultsB2M amyloid fibrils interacted directly with NLRP3/Pyrin and to activate the NLRP3/Pyrin inflammasomes, resulting in IL-1β secretion. When HEK293T cells were transfected with inflammasome components NLRP3 or Pyrin, along with ASC, pro-caspase-1, pro-IL-1β, and B2M, ThT fluorescence intensity increased. This was accompanied by IL-1β secretion, which increased in line with the amount of transfected B2M. In this case, morphological glowing of amyloid fibrils was observed by SEM. In the absence of ASC, there was no increase in ThT fluorescence intensity or IL-1β secretion, or any morphological glowing of amyloid fibrils. NLRP3 or Pyrin and B2M were co-localized in a “speck” in HEK293T cells, and co-expressed in infiltrated monocytes/macrophages in the osteoarticular synovial tissues in a patient with DRA.ConclusionTaken together, these data suggest that inflammasome assembly is required for the subsequent triggering of intracellular formation of B2M amyloid fibrils, which may contribute to osteoarticular deposition of B2M amyloid fibrils and inflammation in patients with DRA.

Pre-Clinical Characterization of a Novel Fusion Protein (AT-03), with Pan-Amyloid Binding and Removal

Background: Amyloidosis is characterized by extracellular deposition of protein fibrils that can involve any organ or tissue in the body. It is a severe, progressive and often lethal disorder. There are approximately seventeen different systemic amyloid diseases, each associated with the deposition of a specific precursor protein. Toxic amyloid deposits result in significant organ dysfunction and increased morbidity and mortality. Reduction and removal of tissue amyloid deposits could restore organ function, improve quality of life and increase life expectancy for patients. We have developed and characterized a fusion protein consisting of serum amyloid protein (SAP) linked to a single chain human IgG1 Fc domain, designated AT-03. SAP is a pentameric serum protein that is ubiquitously associated with amyloid deposits. The high affinity and specificity for amyloid resulted in the use of radio-iodinated SAP as an imaging agent for the non-invasive detection of systemic amyloid. The SAP domain of the fusion protein targets the amyloid deposits delivering Fc domains to stimulate amyloid removal via macrophage mediated phagocytosis.Methods: Binding of AT-03 to ATTR and AL fibrils and extracts was assessed by ELISA. Ex vivo phagocytosis of amyloid substrates was studied using activated human THP-1 cells. The biodistribution of AT-03 in murine models of AA, AApoA2 and AL amyloidosis was evaluated immunohistochemically or by SPECT imaging and microautoradiography. Clearance of AA amyloidosis in response to AT-03 therapy was accessed in a mouse model using histological scoring of amyloid burden.Results: AT-03 bound amyloid AL and ATTR substrates with sub nanomolar EC50 values. Systemic administration of AT-03 resulted in specific binding to diverse forms of amyloid in the heart, kidney, liver and/or spleen in multiple animal models. Opsonization of amyloid deposits with AT-03 in vitro resulted in a dose dependent phagocytosis by activated THP-1 cells. A single IV dose of AT-03 resulted in significant reduction of splenic AA amyloid within 14 days post-injection.Conclusions: We have developed a novel fusion protein with sub nanomolar pan amyloid reactivity that specifically binds diverse forms of amyloid in multiple organs and tissues in vivo and can effectuate amyloid removal. The data indicates that AT-03 may serve as a novel therapeutic for the removal of systemic amyloid deposits of diverse types. AT-03 is currently being developed for clinical evaluation. DisclosuresSirac: Attralus, Inc: Patents & Royalties, Research Funding. Jaccard: Janssen: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Abbvie: Honoraria. Bridoux: AstraZeneca: Consultancy, Speakers Bureau; Janssen: Consultancy. Bell: Attralus Inc: Current Employment. Guthrie: Attralus Inc: Current Employment. Selvarajah: Attralus Inc: Current Employment. Kennel: Attralus Inc: Current holder of stock options in a privately-held company, Patents & Royalties: Inventor and patent holder. Wall: Attralus Inc: Current holder of stock options in a privately-held company, Patents & Royalties: Inventor and patent holder, Research Funding.

Lokalizované formy plicní amyloidózy

Amyloidosis is a rare disorder caused by amyloid deposits in various organs and tissues resulting in vital organ dysfunction, eventually death. There are two forms of amyloidosis - systemic, characterized by multiple organs affected, and localized (focal). Localized forms of amyloidosis usually affect urinary bladder, skin and lungs. Pulmonary amyloidosis may be localized or systemic such as diffuse alveolo-septal pulmonary amyloidosis which usually accompanies systemic AL amyloidosis. Other two forms of pulmonary amyloidosis are tracheobronchial and nodular. All three forms are usually detected by accident when patients undergo chest examination for different reasons as most cases of pulmonary amyloidosis are asymptomatic. The prognosis of localized amyloidosis is good with 5-year overall survival being 90,6 %. In our case report we present three patients diagnosed with localized pulmonary amyloidosis at our center. In all cases the diagnoses were made following the resection of affected lung segments with no further treatment needed.

P-022: Survival benefit observed with Birtamimab in Mayo Stage IV AL amyloidosis supports initiation of confirmatory AFFIRM-AL phase 3 study

<h3>Background</h3> Light chain (AL) amyloidosis is a rare and typically fatal disorder caused by misfolded AL protein, resulting in amyloid deposits in tissues that cause organ dysfunction and failure, most commonly in the heart and kidneys. Birtamimab is an investigational monoclonal antibody designed to indirectly promote phagocytic clearance of amyloid deposits. The phase 3 VITAL study was terminated based on a futility analysis of the composite primary endpoint (time to all-cause mortality [ACM] or time to cardiac hospitalization >90 days after first study drug infusion); the final hazard ratio (HR) numerically favored birtamimab + standard of care (SOC) over placebo + SOC (HR: 0.835, 95% CI: 0.5799, 1.2011; p=0.330). Post hoc analysis of ACM over 9 months revealed a pronounced survival benefit (HR: 0.413, 95% CI: 0.191, 0.895; p=0.025) in patients at high risk for early mortality (Mayo stage IV); proportions of surviving patients were 74% (birtamimab + SOC) and 49% (placebo + SOC). Across all birtamimab trials, no drug-related deaths, dose-limiting toxicities, or major risks were identified. Birtamimab + SOC will provide significant clinical benefit for Mayo stage IV patients with AL amyloidosis versus placebo + SOC (ie, concomitant chemotherapy with a first-line bortezomib-containing regimen). <h3>Methods</h3> The phase 3, double-blind, placebo-controlled AFFIRM-AL study will enroll up to 150 Mayo stage IV patients with newly diagnosed, untreated AL amyloidosis with cardiac involvement. Patients will be randomized 2:1 to receive either intravenous birtamimab + SOC or placebo + SOC. The primary efficacy endpoint of AFFIRM-AL is time to ACM. Safety endpoints include adverse events, clinical laboratory observations, and immunogenicity analyses. <h3>Results</h3> The phase 3 AFFIRM-AL study is designed to confirm this effect of birtamimab under a Special Protocol Assessment agreement with the US FDA. If the study is positive, it would confirm the >50% relative risk reduction for ACM in Mayo stage IV disease observed over 9 months with birtamimab in VITAL. <h3>Conclusions</h3> Birtamimab is the only investigational therapeutic in which a survival benefit has been observed in a post hoc analysis of patients with AL amyloidosis with cardiac involvement. AFFIRM-AL is initiating mid-2021.

Patient-reported outcomes by time from symptom onset to first evidence of pharmacotherapy among patients with transthyretin amyloidosis

Transthyretin amyloidosis (ATTR) is a progressive, systemic, and potentially fatal condition in which misfolded transthyretin proteins form amyloid deposits in muscle and organ tissue. Currently available disease modifying ATTR-related pharmacotherapies generally slow or stop the progression of disease and the benefit of early initiation of treatment has been demonstrated. These analyses examine the relationship between time-to-treatment following symptom onset and long-term patient-reported outcomes (PROs) in patients with ATTR.

Label-Free Infrared Spectroscopic Imaging Reveals Heterogeneity of β-Sheet Aggregates in Alzheimer's Disease.

The aggregation of the amyloid beta (Aβ) protein into plaques is a pathological feature of Alzheimer's disease (AD). While amyloid aggregates have been extensively studied in vitro, their structural aspects and associated chemistry in the brain are not fully understood. In this report, we demonstrate, using infrared spectroscopic imaging, that Aβ plaques exhibit significant heterogeneities in terms of their secondary structure and phospholipid content. We show that the capabilities of discrete frequency infrared imaging (DFIR) are ideally suited for characterization of amyloid deposits in brain tissues and employ DFIR to identify nonplaque β-sheet aggregates distributed throughout brain tissues. We further demonstrate that phospholipid-rich β-sheet deposits exist outside of plaques in all diseased tissues, indicating their potential clinical significance. This is the very first application of DFIR toward a characterization of protein aggregates in an AD brain and provides a rapid, label-free approach that allows us to uncover β-sheet heterogeneities in the AD, which may be significant for targeted therapeutic strategies in the future.

Применение гистохимических красителей для флуоресцентного выявления амилоидных скоплений в тканях человека

Recently, fluorescence microscopy becomes more available, presenting new opportunities to face several challenges of experimental biology and medicine. The study was aimed to assess the effectiveness of fluorescence microscopy for the identification of amyloid deposits in human tissues. Post-mortem samples of the myocardium (n = 12) and cerebral cortex (n = 8) obtained from subjects of both sexes aged 60–98 with verified amyloidosis were used as a material for the study. The specimens were stained using 11 different histochemical dyes and subsequently analyzed by light and fluorescence microscopy. Qualitative and quantitative analysis has shown that Thioflavin T is the most effective stain for fluorescence detection of β- and transthyretin amyloid in human tissues. Congo red staining is highly effective for the detection of transthyretin amyloidosis, however, it is ill-suited for the identification of β-amyloid plaques. It has been found that the ability of Congo red to exhibit fluorescence when binding to amyloid fibrils can be used for verification of amyloid deposits instead of the traditional polarized light microscopy. As has been first noted, methyl violet can selectively bind to β-amyloid with fluorescent complex formation. In addition, methyl violet treatment effectively reduces the autofluorescent background in the nervous tissue. This makes methyl violet staining a promising diagnostic tool for Alzheimer's-type pathology.

Ocular Involvement in Hereditary Amyloidosis.

The term amyloidosis describes a group of rare diseases caused by protein conformation abnormalities resulting in extracellular deposition and accumulation of insoluble fibrillar aggregates. So far, 36 amyloid precursor proteins have been identified, and each one is responsible for a specific disease entity. Transthyretin amyloidosis (ATTRv) is one of the most common forms of systemic and ocular amyloidosis, due to the deposition of transthyretin (TTR), which is a transport protein mainly synthesized in the liver but also in the retinal pigment epithelial cells. ATTRv amyloidosis may be misdiagnosed with several other conditions, resulting in a significant diagnostic delay. Gelsolin and keratoepithelin are other proteins that, when mutated, are responsible for a systemic amyloid disease with significant ocular manifestations that not infrequently appear before systemic involvement. The main signs of ocular amyloid deposition are in the cornea, irido-corneal angle and vitreous, causing complications related to vasculopathy and neuropathy at the local level. This review aims at describing the main biochemical, histopathological and clinical features of systemic amyloidosis associated with eye involvement, with particular emphasis on the inherited forms. We discuss currently available treatments, focusing on ocular involvement and specific ophthalmologic management and highlighting the importance of a prompt treatment for the potential sight-threatening complications derived from amyloid deposition in ocular tissues.

Tenosynovial and Cardiac Transthyretin Amyloidosis in Japanese Patients Undergoing Carpal Tunnel Release.

Background: Wild-type transthyretin cardiac amyloidosis (ATTRwt-CA) is a life-threatening progressive disease. Recent studies have shown that the detection of transthyretin (TTR) amyloid in tenosynovial tissue may play an important role in the diagnosis of cardiac amyloidosis. The aim of this study was to determine the prevalence of TTR amyloid deposits in surgical tissue of patients undergoing carpal tunnel surgery and to clarify the clinical significance of concomitant cardiac examination with 99 mTc-labeled pyrophosphate (99 mTc-PYP) scintigraphy in those patients with TTR deposition.Methods and Results: We evaluated 79 consecutive patients undergoing carpal tunnel release surgery and biopsy of tenosynovial tissue. The mean (±SD) age of the patients at surgery was 71.6±12.5 years (range 30–95 years); 32 patients (41%) were male. TTR amyloid deposition in tenosynovial tissue was observed in 27 patients (34%). Sixteen of those 27 patients underwent 99 mTc-PYP scintigraphy. Of those 16 patients, 3 (19%) had Grade 2 uptake on 99 mTc-PYP scintigraphy. None of the 3 patients with a diagnosis of ATTRwt-CA had apparent cardiac symptoms and left ventricular wall thickness >13 mm.Conclusions: Concomitant cardiac examination with 99 mTc-PYP scintigraphy in patients who had TTR amyloid deposition in tenosynovial tissue resulted in the identification of 19% of patients with a diagnosis of ATTRwt-CA. This diagnostic approach seems to be useful for the early diagnosis of the disease.

Multimodal, label-free fluorescence and Raman imaging of amyloid deposits in snap-frozen Alzheimer\u2019s disease human brain tissue

Alzheimer’s disease (AD) neuropathology is characterized by hyperphosphorylated tau containing neurofibrillary tangles and amyloid-beta (Aβ) plaques. Normally these hallmarks are studied by (immuno-) histological techniques requiring chemical pretreatment and indirect labelling. Label-free imaging enables one to visualize normal tissue and pathology in its native form. Therefore, these techniques could contribute to a better understanding of the disease. Here, we present a comprehensive study of high-resolution fluorescence imaging (before and after staining) and spectroscopic modalities (Raman mapping under pre-resonance conditions and stimulated Raman scattering (SRS)) of amyloid deposits in snap-frozen AD human brain tissue. We performed fluorescence and spectroscopic imaging and subsequent thioflavin-S staining of the same tissue slices to provide direct confirmation of plaque location and correlation of spectroscopic biomarkers with plaque morphology; differences were observed between cored and fibrillar plaques. The SRS results showed a protein peak shift towards the β-sheet structure in cored amyloid deposits. In the Raman maps recorded with 532 nm excitation we identified the presence of carotenoids as a unique marker to differentiate between a cored amyloid plaque area versus a non-plaque area without prior knowledge of their location. The observed presence of carotenoids suggests a distinct neuroinflammatory response to misfolded protein accumulations.

Using digital whole-slide images to evaluate renal amyloid deposition and its association with clinical features and outcomes of AL amyloidosis.

Few data are available quantifying the proportion of amyloid deposition in renal biopsy specimens. The aim of the study is to investigate the correlation between the proportion of amyloid deposition in renal biopsy and clinical characteristics of Chinese patients with immunoglobulin light-chain amyloidosis (AL amyloidosis). 259 patients diagnosed with renalAL amyloidosis between 2003 and 2015 were studied retrospectively. We developed a digital, automated quantification method to evaluate amyloid deposits in glomeruli, vessels and interstitium on digital whole-slide images (WSIs). The associations between the proportion of amyloid-positive area in the renal biopsy and clinical manifestations were analyzed. The proportion (%) of amyloid-positive area in glomeruli, vessels, interstitium and the whole renal tissue were 11.81 ± 11.38, 14.14 ± 14.05, 3.34 ± 5.36 and 4.25 ± 5.77, respectively. The proportion of amyloid deposition in glomeruli, vessels and interstitium was positively correlated with serum creatinine (Scr), estimated glomerular filtration rate (eGFR) and urinary retinol binding protein (RBP). The proportion of glomerular amyloid deposition, age, urinary N-acetyl-b-D-glucosaminidase (NAG) and urinary RBP could independently predict the risk for overall death. The proportion (%) of amyloid-positive area in blood vessels, interstitium and the whole renal tissue, Scr, and urinary RBP were independent risk factors associated with renal survival. A novel digital analysis algorithm was firstly developed to quantify the proportion of amyloid deposits in renal tissues based on digitalWSIs. The degree and localization of amyloid deposits in the kidney evaluated by digitalWSIs may have predictive value in assessing risk of outcome of AL amyloidosis.

Enhanced detection of ATTR amyloid using a nanofibril-based assay

More than 30 proteins and peptides have been found to form amyloid fibrils in human diseases. Fibrils formed by transthyretin (TTR) are associated with ATTR amyloidosis, affecting many vital organs, including the heart and peripheral nervous system. Congo red staining is the gold standard method for detection of amyloid deposits in tissue. However, Congo red staining and amyloid typing methods such as immunofluorescence labelling are limited to relatively large deposits. Detection of small ATTR deposits present at an early stage of the disease could enable timely treatment and prevent severe tissue damage. In this study, we developed an enhanced ATTR amyloid detection method that uses functionalised protein nanofibrils. Using this method, we achieved sensitive detection of monomeric TTR in a microplate immunoassay and immunofluorescence labelling of ex vivo tissue from two patients containing ATTR aggregates. The system's utility was confirmed on sections from a patient with AA amyloidosis and liver sections from inflamed mouse. These results suggest that the detection system constitutes important new technology for highly sensitive detection of microscopic amounts of ATTR amyloid deposited in tissue.

Shoulder pad and macroglossia: "two signs of AL amyloidosis".

“Shoulder pad” sign resulting from deposition of amyloid in the periarticular soft tissue is rare but it is pathognomonic for immunoglobulin amyloidosis (AL). Although the detection remains a challenge, it gives a strong clue leading to prompt diagnosis.

Musculoskeletal pathology as an early warning sign of systemic amyloidosis: a systematic review of amyloid deposition and orthopedic surgery

BackgroundTransthyretin and immunoglobulin light-chain amyloidoses cause amyloid deposition throughout various organ systems. Recent evidence suggests that soft tissue amyloid deposits may lead to orthopedic conditions before cardiac manifestations occur. Pharmacologic treatments reduce further amyloid deposits in these patients. Thus, early diagnosis improves long term survival.Questions/purposesThe primary purpose of this systematic review was to characterize the association between amyloid deposition and musculoskeletal pathology in patients with common orthopedic conditions. A secondary purpose was to determine the relationship between amyloid positive biopsy in musculoskeletal tissue and the eventual diagnosis of systemic amyloidosis.MethodsWe performed a systematic review using PRISMA guidelines. Inclusion criteria were level I-IV evidence articles that analyzed light-chain or transthyretin amyloid deposits in common orthopedic surgeries. Study methodological quality, risk of bias, and recommendation strength were assessed using MINORS, ROBINS-I, and SORT.ResultsThis systematic review included 24 studies for final analysis (3606 subjects). Amyloid deposition was reported in five musculoskeletal pathologies, including carpal tunnel syndrome (transverse carpal ligament and flexor tenosynovium), hip and knee osteoarthritis (synovium and articular cartilage), lumbar spinal stenosis (ligamentum flavum), and rotator cuff tears (tendon). A majority of studies reported a mean age greater than 70 for patients with TTR or AL positive amyloid.ConclusionsThis systematic review has shown the presence of amyloid deposition detected at the time of common orthopedic surgeries, especially in patients ≥70 years old. Subtyping of the amyloid has been shown to enable diagnosis of systemic light-chain or transthyretin amyloidosis prior to cardiac manifestations.Level of evidenceLevel IV.

Oxazolone-induced gastrointestinal disorders enhance the oral transmission of AA amyloidosis in mice.

Amyloid A (AA) amyloidosis is a lethal disease characterized by systemic AA amyloid deposition, and is reported in many animal species. Despite experiments have shown that AA amyloidosis can be transmitted orally, horizontal transmission and cross-species transmission are concerns, the transmission mechanism has been unknown. In this study, we examined the oral transmission efficiency of AA amyloidosis using oxazolone-induced gastrointestinal disorder mice. As a result, the upper or lower gastrointestinal disorder groups developed more severe amyloid deposition in systemic tissues than the group without gastrointestinal disorders. The results of this study suggest that gastrointestinal damage promotes the oral transmission of AA amyloidosis.

Neurofilament Light Chain may Serve As a Biomarker of Neuropathy in Hattr Amyloidosis with Cardiomyopathy

Introduction Hereditary transthyretin-mediated (hATTR) amyloidosis is a progressive, life-threatening disease due to deposition of transthyretin (TTR) amyloid in various organs and tissues. Historically the disease has been described by predominant clinical manifestation of cardiomyopathy (CM) or polyneuropathy (PN), however a majority of patients are known to develop a mixed phenotype. Because of this, PN symptoms may not always be assessed in patients with predominant CM and neuropathy progression may continue. The potential of neurofilament light chain (NfL) as a non-invasive biomarker of nerve damage in patients with hATTR amyloidosis with PN has previously been described; however to date no studies have investigated NfL in patients with predominant CM. Hypothesis NfL may serve as a biomarker of co-existing neuropathy in patients with hATTR amyloidosis with predominant CM and could lead to early detection and treatment of nerve damage, thus improving patient care. Methods Plasma NfL levels were measured in baseline samples from patients with hATTR amyloidosis with CM from the Phase 3 ENDEAVOUR study (n = 194; V122I variant = 111) and compared with NfL levels from healthy controls (n = 53) and baseline samples from patients with hATTR amyloidosis with PN from the Phase 3 APOLLO study (n = 193). Polyneuropathy Disability (PND) score was also taken into account for NfL analyses. Results Elevated plasma NfL levels were observed in patients with hATTR amyloidosis with CM relative to healthy controls (54.1 pg/mL vs 16.3 pg/mL, p 0 (n = 101; evidence of neurological impairment) were not significantly different to those in patients with hATTR amyloidosis with PN (p = 0.15), where all patients had a PND>0. Patients with hATTR amyloidosis with CM and the V122I variant, generally considered to cause a predominant CM phenotype, also had elevated plasma NfL levels relative to healthy controls (44.9 pg/mL vs 16.3 pg/mL, p Conclusions NfL may serve as a biomarker of nerve damage in patients with hATTR amyloidosis, regardless of the predominant manifestation. This analysis also suggests PN may be underdiagnosed in patients with predominant CM, such as those with a V122I variant, and NfL may be a useful biomarker to support earlier diagnosis of PN in these patients.

Direct measurement of lipid membrane disruption connects kinetics and toxicity of Aβ42 aggregation.

The formation of amyloid deposits in human tissues is a defining feature of more than 50 medical disorders, including Alzheimer's disease. Strong genetic and histological evidence links these conditions to the process of protein aggregation, yet it has remained challenging to identify a definitive connection between aggregation and pathogenicity. Using time-resolved fluorescence microscopy of individual synthetic vesicles, we show for the Aβ42 peptide implicated in Alzheimer's disease that the disruption of lipid bilayers correlates linearly with the time course of the levels of transient oligomers generated through secondary nucleation. These findings indicate a specific role of oligomers generated through the catalytic action of fibrillar species during the protein aggregation process in driving deleterious biological function and establish a direct causative connection between amyloid formation and its pathological effects.

Polymer materials as promoters/inhibitors of amyloid fibril formation

Polymers are omnipresent materials that are widely used in medicine, e.g., as construction materials for medical devices or as polymer nanoparticle drug delivery systems. Therefore, their possible effects on biomolecules, such as lipids, proteins, and other molecules, present in the human body must be examined. This review addresses the effects of polymer materials (such as dendrimers, polysaccharides) on the process of amyloid fibril formation. Amyloidoses are very serious diseases that are characterized by amyloid deposition in various organs and tissues, causing their dysfunction. The treatment of amyloidoses, such as Alzheimer’s disease (AD), using polymer materials is a challenge. Studies aiming to elucidate the effects of polymers on the process of amyloid fibril formation are therefore also of key importance for understanding the process of amyloid fibril formation and amyloidoses in general.