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Biomarkers of axonal damage to favor early diagnosis in variant transthyretin amyloidosis (A-ATTRv).Scientific Reports Jan 2024Early identification of ATTRv amyloidosis disease onset is still often delayed due to the lack of validated biomarkers of this disease. Light chain neurofilament (NfL)...
Early identification of ATTRv amyloidosis disease onset is still often delayed due to the lack of validated biomarkers of this disease. Light chain neurofilament (NfL) have shown promising results in early diagnosis in this disease, but data is still needed, including with alternative measuring methods. Our aim was to study the levels of NfL measured by ELISA. Furthermore, interstitial matrix metalloproteinase type 1 (MMP-1) serum levels were measured as a potential new biomarker in ATTRv. Serum NfL and MMP-1 were measured using ELISA assays in 90 participants (29 ATTR-V30M patients, 31 asymptomatic V30M-TTR variant carriers and 30 healthy controls). Median NfL levels among ATTRv amyloidosis patients were significantly higher (116 pg/mL vs 0 pg/mL in both comparison groups). The AUC comparing ATTRv amyloidosis patients and asymptomatic carriers was 0.90 and the NfL concentration of 93.55 pg/mL yielded a sensitivity of 79% and a specificity of 87%. NfL levels had a significant positive correlation with NIS values among patients. We found a negative significant correlation between eGFR and NfL levels. Finally, MMP1 levels were not different between groups. Evidence of NfL use for early diagnosis of ATTR-PN amyloidosis is growing. ELISA seems a reliable and available technique for it quantification. Decreased GFR could influence NfL plasma levels.
Topics: Humans; Matrix Metalloproteinase 1; Amyloid Neuropathies, Familial; Early Diagnosis; Biomarkers
PubMed: 38182630
DOI: 10.1038/s41598-023-50212-2 -
International Journal of Cardiology May 2024Cardiac amyloidosis is increasingly recognized as a significant contributor to cardiovascular morbidity and mortality. With the emergence of novel therapies, there is a... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Cardiac amyloidosis is increasingly recognized as a significant contributor to cardiovascular morbidity and mortality. With the emergence of novel therapies, there is a growing interest in prognostication of patients with cardiac amyloidosis using cardiac magnetic resonance imaging (CMR). In this systematic review and meta-analysis, we aimed to examine the prognostic significance of myocardial native T1 and T2, and extracellular volume (ECV).
METHODS
Observational cohort studies or single arms of clinical trials were eligible. MEDLINE, EMBASE and CENTRAL were systematically searched from their respective dates of inception to January 2023. No exclusions were made based on date of publication, study outcomes, or study language. The study populations composed of adult patients (≥18 years old) with amyloid cardiomyopathy. All studies included the use of CMR with and without intravenous gadolinium contrast administration to assess myocardial native T1 mapping, T2 mapping, and ECV in association with the pre-specified primary outcome of all-cause mortality. Data were extracted from eligible primary studies by two independent reviewers and pooled via the inverse variance method using random effects models for meta-analysis.
RESULTS
A total of 3852 citations were reviewed. A final nine studies including a total of 955 patients (mean age 65 ± 10 years old, 32% female, mean left ventricular ejection fraction (LVEF) 59 ± 12% and 24% had NYHA class III or IV symptoms) with cardiac amyloidosis [light chain amyloidosis (AL) 50%, transthyretin amyloidosis (ATTR) 49%, other 1%] were eligible for inclusion and suitable for data extraction. All included studies were single centered (seven with 1.5 T MRI scanners, two with 3.0 T MRI scanners) and non-randomized in design, with follow-up spanning from 8 to 64 months (median follow-up = 25 months); 320 patients died during follow-up, rendering a weighted mortality rate of 33% across studies. Compared with patients with AL amyloid, patients with ATTR amyloid had significantly higher mean left ventricular mass index (LVMi) (102 ± 34 g/m vs 127 ± 37 g/m, p = 0.02). N-terminal pro-brain natriuretic peptide (NT-proBNP), troponin T levels, mean native T1 values, ECV and T2 values did not differ between patients with ATTR amyloid and AL amyloid (all p > 0.25). Overall, the hazard ratios for mortality were 1.33 (95% CI = [1.10, 1.60]; p = 0.003; I = 29%) for every 60 ms higher T1 time, 1.16 (95% CI = [1.09, 1.23], p < 0.0001; I = 76%) for every 3% higher ECV, and 5.23 (95% CI = [2.27, 12.02]; p < 0.0001; I = 0%) for myocardial-to-skeletal T2 ratio below the mean (vs above the mean).
CONCLUSION
Higher native T1 time and ECV, and lower myocardial to skeletal T2 ratio, on CMR are associated with worse mortality in patients with cardiac amyloidosis. Therefore, tissue mapping using CMR may offer a useful non-invasive technique to monitor disease progression and determine prognosis in patients with cardiac amyloidosis.
Topics: Adult; Humans; Female; Middle Aged; Aged; Adolescent; Male; Cardiomyopathies; Stroke Volume; Ventricular Function, Left; Magnetic Resonance Imaging; Myocardium; Amyloid Neuropathies, Familial; Disease Progression; Magnetic Resonance Imaging, Cine; Predictive Value of Tests; Contrast Media; Observational Studies as Topic
PubMed: 38382853
DOI: 10.1016/j.ijcard.2024.131892 -
BioRxiv : the Preprint Server For... May 2024ATTR amyloidosis is a systemic disease characterized by the deposition of amyloid fibrils made of transthyretin, a protein integral to transporting retinol and thyroid...
ATTR amyloidosis is a systemic disease characterized by the deposition of amyloid fibrils made of transthyretin, a protein integral to transporting retinol and thyroid hormones. Transthyretin is primarily produced by the liver and circulates in blood as a tetramer. The retinal epithelium also secretes transthyretin, which is secreted to the vitreous humor of the eye. Because of mutations or aging, transthyretin can dissociate into amyloidogenic monomers triggering amyloid fibril formation. The deposition of transthyretin amyloid fibrils in the myocardium and peripheral nerves causes cardiomyopathies and neuropathies, respectively. Using cryo-electron microscopy, here we determined the structures of amyloid fibrils extracted from cardiac and nerve tissues of an ATTRv-V30M patient. We found that fibrils from both tissues share a consistent structural conformation, similar to the previously described structure of cardiac fibrils from an individual with the same genotype, but different from the fibril structure obtained from the vitreous humor. Our study hints to a uniform fibrillar architecture across different tissues within the same individual, only when the source of transthyretin is the liver. Moreover, this study provides the first description of ATTR fibrils from the nerves of a patient and enhances our understanding of the role of deposition site and protein production site in shaping the fibril structure in ATTRv-V30M amyloidosis.
PubMed: 38798361
DOI: 10.1101/2024.05.14.594028 -
The Journal of Physical Chemistry... Dec 2023Transthyretin (TTR) is a small tetrameric protein that aggregates, forming highly toxic oligomers and fibrils. In the blood and cerebrospinal fluid, TTR can interact...
Transthyretin (TTR) is a small tetrameric protein that aggregates, forming highly toxic oligomers and fibrils. In the blood and cerebrospinal fluid, TTR can interact with various biomolecules, phospho- and sphingolipids, and cholesterol on the red blood cell plasma membrane. However, the role of these molecules in TTR aggregation remains unclear. In this study, we investigated the extent to which phosphatidylcholine (PC), sphingomyelin (SM), and cholesterol (Cho), important components of plasma membranes, could alter the rate of TTR aggregation. We found that PC and SM inhibited TTR aggregation whereas Cho strongly accelerated it. The presence of these lipids during the stage of protein aggregation uniquely altered the morphology and secondary structure of the TTR fibrils, which changed the toxicity of these protein aggregates. These results suggest that interactions of TTR with red blood cells, whose membranes are rich with these lipids, can trigger irreversible aggregation of TTR and cause transthyretin amyloidosis.
Topics: Humans; Amyloid; Sphingomyelins; Prealbumin; Amyloid Neuropathies, Familial; Protein Aggregates; Cholesterol
PubMed: 38033106
DOI: 10.1021/acs.jpclett.3c02613 -
Vaccines Nov 2023Alzheimer disease (AD) is one of the most common and disabling neuropathies in the ever-growing aged population around the world, that especially affects Western...
Alzheimer disease (AD) is one of the most common and disabling neuropathies in the ever-growing aged population around the world, that especially affects Western countries. We are in urgent need of finding an effective therapy but also a valid prophylactic means of preventing AD. There is a growing attention currently paid to DNA vaccination, a technology particularly used during the COVID-19 era, which can be used also to potentially prevent or modify the course of neurological diseases, including AD. This paper aims to discuss the main features and hurdles encountered in the immunization and therapy against AD using DNA vaccine technology. Ultimately, this work aims to effectively promote the efforts in research for the development of safe and effective DNA and RNA vaccines for AD.
PubMed: 38006038
DOI: 10.3390/vaccines11111706 -
ACS Chemical Neuroscience Sep 2023The progressive accumulation of transthyretin (TTR), a small protein that transports thyroxine, in various organs and tissues is observed upon transthyretin amyloidosis,...
The progressive accumulation of transthyretin (TTR), a small protein that transports thyroxine, in various organs and tissues is observed upon transthyretin amyloidosis, a severe pathology that affects the central, peripheral, and autonomic nervous systems. Once expressed in the liver and choroid plexus, TTR is secreted into the bloodstream and cerebrospinal fluid. In addition to thyroxine, TTR interacts with a large number of molecules, including retinol-binding protein and lipids. In this study, we examined the extent to which phosphatidylserine (PS), a phospholipid that is responsible for the recognition of apoptotic cells by macrophages, could alter the stability of TTR. Using thioflavin T assay, we investigated the rates of TTR aggregation in the presence of PS with different lengths and saturation of fatty acids (FAs). We found that all analyzed lipids decelerated the rate of TTR aggregation. We also used a set of biophysical methods to investigate the extent to which the presence of PS altered the morphology and secondary structure of TTR aggregates. Our results showed that the length and saturation of fatty acids in PS uniquely altered the morphology and secondary structure of TTR fibrils. As a result, TTR fibrils that were formed in the presence of PS with different lengths and saturation of FAs exerted significantly lower cell toxicity compared with the TTR aggregates grown in the lipid-free environment. These findings help to reveal the role of PS in transthyretin amyloidosis and determine the role of the length and saturation of FAs in PS on the morphology and secondary structure of TTR fibrils.
Topics: Humans; Prealbumin; Fatty Acids; Phosphatidylserines; Thyroxine; Amyloid Neuropathies, Familial
PubMed: 37676231
DOI: 10.1021/acschemneuro.3c00357 -
Circulation Journal : Official Journal... Jun 2024The prevalence of transthyretin amyloid cardiomyopathy (ATTR-CM) in atrial fibrillation (AF) patients remains unclear. We explored the efficacy of computed...
Efficacy of Computed Tomography-Based Evaluation of Myocardial Extracellular Volume Combined With Red Flags for Early Screening of Concealed Cardiac Amyloidosis in Patients With Atrial Fibrillation.
BACKGROUND
The prevalence of transthyretin amyloid cardiomyopathy (ATTR-CM) in atrial fibrillation (AF) patients remains unclear. We explored the efficacy of computed tomography-based myocardial extracellular volume (CT-ECV) combined with red flags for the early screening of concealed ATTR-CM in AF patients undergoing catheter ablation.Methods and Results: Patients referred for AF ablation at Oita University Hospital were prescreened using the red-flag signs defined by echocardiographic or electrocardiographic findings, medical history, symptoms, and blood biochemical findings. Myocardial CT-ECV was quantified in red flag-positive patients using routine pre-AF ablation planning cardiac CT with the addition of delayed-phase cardiac CT scans. Patients with high (>35%) ECV were evaluated using technetium pyrophosphate (Tc-PYP) scintigraphy. A cardiac biopsy was performed during the planned AF ablation procedure if Tc-PYP scintigraphy was positive. Between June 2022 and June 2023, 342 patients were referred for AF ablation. Sixty-seven (19.6%) patients had at least one of the red-flag signs. Myocardial CT-ECV was evaluated in 57 patients because of contraindications to contrast media, revealing that 16 patients had high CT-ECV. Of these, 6 patients showed a positive Tc-PYP study, and 6 patients were subsequently diagnosed with wild-type ATTR-CM via cardiac biopsy and genetic testing.
CONCLUSIONS
CT-ECV combined with red flags could contribute to the systematic early screening of concealed ATTR-CM in AF patients undergoing catheter ablation.
Topics: Humans; Atrial Fibrillation; Male; Female; Aged; Middle Aged; Amyloid Neuropathies, Familial; Cardiomyopathies; Catheter Ablation; Myocardium; Tomography, X-Ray Computed; Early Diagnosis
PubMed: 38522901
DOI: 10.1253/circj.CJ-23-0948 -
Cureus Feb 2024Familial amyloidotic polyneuropathy (FAP) is an autosomal dominant hereditary disorder. In Portugal, it is mainly linked to transthyretin (TTR) mutation, and patients...
Familial amyloidotic polyneuropathy (FAP) is an autosomal dominant hereditary disorder. In Portugal, it is mainly linked to transthyretin (TTR) mutation, and patients present with length-dependent sensory-motor polyneuropathy, often accompanied by autonomic dysfunction. Treatment options for FAP include liver transplant, and due to the lack of organs, FAP livers began being implanted in patients with severe liver disease in a process known as domino liver transplantation (DLT). We report a case of a 68-year-old Portuguese man, with post-hepatitis C-related cirrhosis liver transplantation, who presented to his family doctor with decreased sensitivity in both feet and weight loss, which were initially attributed to diabetic neuropathy and an adjustment in diabetic medication, respectively. Symptoms evolved to changes in both feet's thermal and painful sensitivity, reduced sensitivity in both hands, diarrhea, and progressive weight loss. At this time, the patient's disclosure of receiving a DLT prompted the correct diagnosis of iatrogenic amyloid polyneuropathy. This case underscores the challenges in diagnosing and managing iatrogenic amyloid polyneuropathy following DLT, highlighting the importance of prompt identification of DLT recipients, active vigilance of these patients via structured monitoring, and increased healthcare providers' awareness of this practice so that early signs of the disease may be recognized.
PubMed: 38449948
DOI: 10.7759/cureus.53605 -
Scientific Reports Aug 2023This study reports the long-term results of trabeculectomy (LEC) for secondary glaucoma in hereditary transthyretin (ATTRv) amyloidosis patients and its correlation with...
This study reports the long-term results of trabeculectomy (LEC) for secondary glaucoma in hereditary transthyretin (ATTRv) amyloidosis patients and its correlation with prior vitrectomy. A retrospective case series was conducted involving 31 consecutive eyes of 20 ATTRv amyloidosis patients who underwent LEC between 2007 and 2020. The mean follow-up period was 73.2 ± 37.0 months (range: 20-181 months). Postoperative intraocular pressures (IOPs) were evaluated based on the following criteria: (a) IOP between 6 and 21 mmHg without additional glaucoma surgeries, except for laser suture lysis, (b) IOP between 6 and 15 mmHg without additional glaucoma surgeries, except for laser suture lysis, and (c) IOP between 6 and 21 mmHg without additional glaucoma surgeries, except for needling and laser suture lysis. Kaplan-Meier analysis revealed survival rates after LEC of 0.52 at 36 months, 0.42 at 60 months, and 0.25 at 84 months under criterion (a); 0.49 at 36 months, 0.27 at 60 months, and 0.11 at 84 months under criterion (b); and 0.76 at 36 months, 0.71 at 60 months, and 0.65 at 84 months under criterion (c). Eyes with a history of small gauge transconjunctival vitrectomy (SGTV) exhibited a tendency towards lower survival rates, although no statistically significant difference was observed (log-rank test; p = 0.193 under criterion (a) and p = 0.0553 under criterion (b)). Our findings suggest that LEC and additional needling procedures can provide some control over IOP; however, the overall postoperative outcomes of LEC for ATTRv amyloidosis remain unsatisfactory, even in the era of SGTV with reduced conjunctival scarring.
Topics: Humans; Trabeculectomy; Retrospective Studies; Glaucoma; Amyloid Neuropathies, Familial; Intraocular Pressure; Treatment Outcome; Follow-Up Studies
PubMed: 37550352
DOI: 10.1038/s41598-023-40029-4