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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 -
Common transthyretin-derived amyloid fibril structures in patients with hereditary ATTR amyloidosis.Nature Communications Nov 2023Systemic ATTR amyloidosis is an increasingly important protein misfolding disease that is provoked by the formation of amyloid fibrils from transthyretin protein. The...
Systemic ATTR amyloidosis is an increasingly important protein misfolding disease that is provoked by the formation of amyloid fibrils from transthyretin protein. The pathological and clinical disease manifestations and the number of pathogenic mutational changes in transthyretin are highly diverse, raising the question whether the different mutations may lead to different fibril morphologies. Using cryo-electron microscopy, however, we show here that the fibril structure is remarkably similar in patients that are affected by different mutations. Our data suggest that the circumstances under which these fibrils are formed and deposited inside the body - and not only the fibril morphology - are crucial for defining the phenotypic variability in many patients.
Topics: Humans; Amyloid; Amyloid Neuropathies, Familial; Cryoelectron Microscopy; Prealbumin; Proteostasis Deficiencies
PubMed: 37993462
DOI: 10.1038/s41467-023-43301-3 -
Orphanet Journal of Rare Diseases Nov 2023Hereditary transthyretin amyloidosis (ATTRv) is a rare genetic disease that negatively affects patients' quality of life through the involvement of various organs and...
BACKGROUND
Hereditary transthyretin amyloidosis (ATTRv) is a rare genetic disease that negatively affects patients' quality of life through the involvement of various organs and tissues. Despite a large amount of research on medical and psychosocial interventions, the impact of occupational therapy (OT) on patients with ATTRv is not well understood.
OBJECTIVE
The aim of this study was to develop an OT programme to improve the daily functioning and quality of life of patients with ATTRv.
METHODS
Fourteen patients with ATTRv were interviewed. Together they developed short- and medium-term occupational goals. Patients received the OT intervention for six months. Outcomes were measured using scores for activities of daily living and psychological well-being.
RESULTS
The study found that OT can have a positive impact as a complementary intervention to medical and other psychosocial treatments. Of the 14 patients, 12 maintained the same scores in activities of daily living. Two deteriorated and eight improved their psychological scores.
CONCLUSION
This study highlights the need for further research in this area and the importance of OT in the management of patients with ATTRv. Early intervention is of paramount importance and further research is needed to evaluate the long-term effects of OT interventions in patients with ATTRv.
Topics: Humans; Activities of Daily Living; Quality of Life; Amyloid Neuropathies, Familial; Qualitative Research; Rare Diseases
PubMed: 37950297
DOI: 10.1186/s13023-023-02964-3 -
Orphanet Journal of Rare Diseases Nov 2023Transthyretin amyloidosis (ATTR amyloidosis) is a progressive, multisystemic, life-threatening disease resulting from the deposition of variant or wild-type (ATTRwt... (Observational Study)
Observational Study
BACKGROUND
Transthyretin amyloidosis (ATTR amyloidosis) is a progressive, multisystemic, life-threatening disease resulting from the deposition of variant or wild-type (ATTRwt amyloidosis) transthyretin amyloid fibrils in various tissues and organs.
METHODS
Established in 2007, the Transthyretin Amyloidosis Outcomes Survey (THAOS) is the largest ongoing, global, longitudinal, observational study of patients with ATTR amyloidosis, including both hereditary and wild-type disease, and asymptomatic carriers of pathogenic TTR mutations. This analysis describes the baseline characteristics of symptomatic patients and asymptomatic gene carriers enrolled in THAOS since its inception in 2007 (data cutoff: August 1, 2022), providing a consolidated overview of 15-year data from the THAOS registry.
RESULTS
This analysis included 4428 symptomatic patients and 1707 asymptomatic gene carriers. The majority of symptomatic patients were male (70.8%) with a mean (standard deviation [SD]) age at symptom onset of 56.6 (17.9) years. Compared with the 14-year analysis, V30M remained the most prevalent genotype in Europe (62.2%), South America (78.6%), and Japan (74.2%) and ATTRwt remained most common in North America (56.2%). Relative to the 14-year analysis, there was an increase of mixed phenotype (from 16.6 to 24.5%) and a reduction of predominantly cardiac phenotype (from 40.7 to 31.9%). The proportion of patients with predominantly neurologic phenotype remained stable (from 40.1 to 38.7%). Asymptomatic gene carriers were 58.5% female with a mean age at enrollment of 41.9 years (SD 15.5).
CONCLUSIONS
This overview of > 6000 patients enrolled over 15 years in THAOS represents the largest registry analysis of ATTR amyloidosis to date and continues to emphasize the genotypic and phenotypic heterogeneity of the disease. Nearly a quarter of the symptomatic population within THAOS was mixed phenotype, underscoring the need for multidisciplinary management of ATTR amyloidosis.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT00628745.
Topics: Adult; Female; Humans; Male; Middle Aged; Amyloid Neuropathies, Familial; Longitudinal Studies; Prealbumin; Registries; Surveys and Questionnaires
PubMed: 37946256
DOI: 10.1186/s13023-023-02962-5 -
JACC. Heart Failure Jan 2024Tafamidis was approved to treat patients with transthyretin amyloid cardiomyopathy (ATTR-CM) on the basis of findings from the phase 3 Tafamidis in Transthyretin...
BACKGROUND
Tafamidis was approved to treat patients with transthyretin amyloid cardiomyopathy (ATTR-CM) on the basis of findings from the phase 3 Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT).
OBJECTIVES
This study was a post hoc analysis exploring tafamidis efficacy in octogenarian patients.
METHODS
Analysis of patients aged <80 and ≥80 years in ATTR-ACT and its ongoing open-label long-term extension (LTE) study, where all patients receive tafamidis.
RESULTS
After 30 months in ATTR-ACT, least squares (LS) mean change from baseline in 6-minute walk test (6MWT) distance, N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentration, and Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS) score were smaller (all P < 0.05) in patients aged ≥80 years treated with tafamidis (n = 51) vs placebo (n = 37). At the LTE study interim analysis, patients aged ≥80 years treated continuously with tafamidis had a smaller decline in KCCQ-OS score (P < 0.05) and trended toward longer median survival (45 vs 27 months; all-cause mortality HR: 0.6828 [95% CI: 0.4048-1.1517]; P = 0.1526) than those initially treated with placebo in ATTR-ACT. Similar efficacy was observed in patients aged <80 years in ATTR-ACT, including smaller LS mean change from baseline in 6MWT distance, NT-proBNP concentration, and KCCQ-OS score, and lower rate of cardiovascular-related hospitalizations with tafamidis (n = 125) vs placebo (n = 140). In the LTE study, patients aged <80 years treated continuously with tafamidis had a longer median survival (80 vs 41 months; HR = 0.4513 [95% CI: 0.3176-0.6413]; P < 0.0001) and a smaller decline in KCCQ-OS score than those initially treated with placebo.
CONCLUSIONS
The findings demonstrate tafamidis efficacy for patients with ATTR-CM both in those aged <80 and those aged ≥80 years. (Tafamidis in Transthyretin Cardiomyopathy Clinical Trial [ATTR-ACT]; NCT01994889/Long-term Safety of Tafamidis in Subjects With Transthyretin Cardiomyopathy; NCT02791230).
Topics: Aged; Aged, 80 and over; Humans; Amyloid Neuropathies, Familial; Cardiomyopathies; Heart Failure; Octogenarians; Prealbumin; Clinical Trials, Phase III as Topic
PubMed: 37943223
DOI: 10.1016/j.jchf.2023.08.032 -
Neurological Sciences : Official... Apr 2024Hereditary transthyretin (ATTRv) amyloidosis is a heterogeneous, progressive, multisystemic disease with a life-threatening course if left untreated. Given the current...
BACKGROUND
Hereditary transthyretin (ATTRv) amyloidosis is a heterogeneous, progressive, multisystemic disease with a life-threatening course if left untreated. Given the current availability of effective therapies, close follow-up of presymptomatic TTR mutation carriers is essential to recognize disease onset at the earliest sign. In addition to routine techniques, in recent years several novel tools have been proposed, although a consensus on their use has not been reached yet. In this paper, we aimed to evaluate possible markers of neuropathic disease onset intended to discriminate clinically asymptomatic carriers from early symptomatic patients, thus allowing timely treatment initiation.
METHODS
Thirty-eight presymptomatic carriers were enrolled. Clinical and electrophysiological findings at first evaluation and follow-up were collected. All carriers underwent an extensive clinical and instrumental evaluation according to the standard clinical practice. One or more non-routine investigations, whose use in this field is not yet validated (henceforth "unconventional"), were additionally assessed in a subgroup of individuals.
RESULTS
Based on the exclusive use of routine investigations, it was possible to define disease onset in 4/38 carriers during the follow-up. Employing additionally one or more "unconventional" tests, abnormal findings, indicative of a possible "conversion" to symptomatic disease, were detected in further 12 cases. More than half of our study cohort showed findings suggestive of small nerve fiber (SF) involvement at either invasive or non-invasive tests.
CONCLUSIONS
A close, multidisciplinary monitoring of presymptomatic TTR mutation carriers is fundamental, and diagnostic workup should include both routine and "unconventional" tests. Assessment of SF involvement is important also in non-endemic countries.
Topics: Humans; Amyloid Neuropathies, Familial; Prealbumin; Early Diagnosis; Mutation
PubMed: 37938457
DOI: 10.1007/s10072-023-07177-x -
Orphanet Journal of Rare Diseases Nov 2023Precise data about ATTR-CM incidence rates at national level are scarce. Consequently, this study aimed to estimate the annual incidence and survival of transthyretin...
BACKGROUND
Precise data about ATTR-CM incidence rates at national level are scarce. Consequently, this study aimed to estimate the annual incidence and survival of transthyretin amyloid cardiomyopathy (ATTR-CM) in France between 2011 and 2019 using real world data. We used the French nationwide exhaustive data (SNDS database) gathering in- and out-patient claims. As there is no specific ICD-10 marker code for ATTR-CM, diagnosis required both amyloidosis (identified by E85. ICD-10 code or a tafamidis meglumine delivery) and a cardiovascular condition (identified by ICD-10 or medical procedure codes related to either heart failure, arrhythmias, conduction disorders or cardiomyopathies), not necessarily reported at the same visit. Patients with probable AL-form of amyloidosis or probable AA-form of amyloidosis were excluded.
RESULTS
Between 2011 and 2019, 8,950 patients with incident ATTR-CM were identified. Incidence rates increased from 0.6 / 100,000 person-years in 2011 to 3.6 / 100,000 person-years in 2019 (p < 0.001), reaching 2377 new cases in 2019. Sex ratios (M/F) increased from 1.52 in 2011 to 2.23 in 2019. In 2019, median age at diagnosis was 84.0 years (85.5 for women and 83.5 for men). Median survival after diagnosis was 41.9 months (95% CI [39.6, 44.1]).
CONCLUSIONS
This is the first estimate of nationwide ATTR-CM incidence in France using comprehensive real-world databases. We observed an increased incidence over the study period, consistent with an improvement in ATTR-CM diagnosis in recent years.
Topics: Female; Humans; Male; Amyloid Neuropathies, Familial; Cardiomyopathies; Incidence; Outpatients; Prealbumin; Aged; France
PubMed: 37926810
DOI: 10.1186/s13023-023-02933-w -
Revista Portuguesa de Cardiologia :... Mar 2024
Topics: Humans; Amyloid Neuropathies, Familial; Radionuclide Imaging
PubMed: 37923243
DOI: 10.1016/j.repc.2023.07.007 -
Canadian Journal of Kidney Health and... 2023transplant amyloidosis denotes the condition when a patient develops amyloidosis after transplantation but had not been diagnosed with the disease prior to...
RATIONALE
transplant amyloidosis denotes the condition when a patient develops amyloidosis after transplantation but had not been diagnosed with the disease prior to transplantation. The incidence of amyloidosis in kidney transplants is rare, but few published case reports have described the occurrence of Amyloid A protein (AA) and Light Chain (AL) amyloidosis. However, hereditary fibrinogen A alpha chain (AFib) has not been previously reported.
PATIENT PRESENTATION
We present a 72-year-old man, a kidney transplant recipient, who developed progressive rise in his creatinine about 3 years after transplantation. He has long-standing diabetes mellitus type 2, obesity, and hypertension, so he did not have a kidney biopsy of his native kidneys prior to transplantation.
DIAGNOSIS
A kidney transplant biopsy was done that showed amyloidosis. Mass spectrophotometry confirmed it as AFib amyloidosis. Genetic testing of the patient revealed that he has fibrinogen A alpha gene (FGA) point mutation with a p.E545V variant.
INTERVENTIONS
Cardiac evaluation showed normal transthoracic echocardiogram. Cardiac magnetic resonance imaging (MRI) showed no involvement by amyloidosis. A peripheral nerve biopsy showed diabetic neuropathy. Thus, the kidney was the only organ involved by the disease. The kidney transplant was managed conservatively with blood pressure and diabetes control in addition to his usual immunosuppression regimen which was not altered. He is being treated with diuretics, angiotensin receptor inhibitors, and sodium glucose transport 2 inhibitors.
OUTCOMES
Kidney transplant function exhibited only slow progression over 18 months since the diagnosis was confirmed. This slow progression is likely because the p.E545V point mutation variant is less aggressive than other gene deletion mutations and because our patient was judged to have been diagnosed early in the course of his disease.
TEACHING POINTS
In this case report, we illustrate the findings and testing that confirmed the diagnosis of AFib amyloidosis. We summarize the clinical aspects, outcomes of the disease, and treatment options. We believe this case report is interesting because it is the first reported case of AFib amyloidosis in a kidney transplant recipient who was not known to have the disease prior to kidney transplantation.
PubMed: 37920778
DOI: 10.1177/20543581231209207 -
Annals of Clinical and Translational... Jan 2024Despite amyloid deposition as a hallmark of hereditary transthyretin amyloidosis (ATTRv) with polyneuropathy, this pathology could not completely account for nerve...
OBJECTIVE
Despite amyloid deposition as a hallmark of hereditary transthyretin amyloidosis (ATTRv) with polyneuropathy, this pathology could not completely account for nerve degeneration. ATTRv patients frequently have vasomotor symptoms, but microangiopathy hypothesis in ATTRv was not systemically clarified.
METHODS
This study examined the vascular pathology of sural nerves in ATTRv patients with transthyretin (TTR) mutation of p.Ala117Ser (TTR-A97S), focusing on morphometry and patterns of molecular expression in relation to nerve degeneration. We further applied human microvascular endothelial cell (HMEC-1) culture to examine the direct effect of TTR-A97S protein on endothelial cells.
RESULTS
In ATTRv nerves, there was characteristic microangiopathy compared to controls: increased vessel wall thickness and decreased luminal area; both were correlated with the reduction of myelinated fiber density. Among the components of vascular wall, the area of collagen IV in ATTRv nerves was larger than that of controls. This finding was validated in a cell model of HMEC-1 culture in which the expression of collagen IV was upregulated after exposure to TTR-A97S. Apoptosis contributed to the endothelial cell degeneration of microvasculatures in ATTRv endoneurium. ATTRv showed prothrombotic status with intravascular fibrin deposition, which was correlated with (1) increased tissue factor and coagulation factor XIIIA and (2) reduced tissue plasminogen activator. This cascade led to intravascular thrombin deposition, which was colocalized with upregulated p-selectin and thrombomodulin, accompanied by complement deposition and macrophages infiltration, indicating thromboinflammation in ATTRv.
INTERPRETATION
Microangiopathy with thromboinflammation is characteristic of advanced-stage ATTRv nerves, which provides an add-on mechanism and therapeutic target for nerve degeneration.
Topics: Humans; Tissue Plasminogen Activator; Thromboinflammation; Endothelial Cells; Inflammation; Thrombosis; Nerve Degeneration; Collagen; Amyloid Neuropathies, Familial
PubMed: 37902278
DOI: 10.1002/acn3.51930