Abnormal Protein Deposition Research Articles

Delays in diagnosis and treatment initiation of ATTR cardiac amyloidosis: a real-world data analysis

Abstract Introduction Cardiac amyloidosis (CA) is a serious condition characterized by the accumulation of abnormal protein deposits in the heart muscle, leading to functional impairments and, ultimately, heart failure. Transthyretin amyloid cardiomyopathy (ATTR-CM) is the most common form encountered in CA diagnosis with previously underestimated prevalence. ATTR-CM poses a diagnostic challenge, with a substantial number of cases diagnosed late and at advanced stages. The availability of specific pharmacological treatment using the transthyretin-stabilizer tafamidis further emphasizes the need for timely diagnosis. Here, we aim to assess delays in diagnosis and initiation of therapy in a real-world collective of patients with ATTR-CM. Methods All individuals diagnosed from 01/2018 to 05/2023 with ATTR-CM at our university hospital, Germany, were systematically assessed for eligibility in this study. Specifically, we enrolled patients who were undergoing transthyretin stabilizer therapy. The investigation aimed to determine the duration, in days, from the initial suspicion of heart disease to the definitive diagnosis of ATTR-CM. It was also investigated whether the diagnosis of ATTR-CM was made more quickly over time as awareness increased. Additionally, the study assessed the time elapsed until patients received pharmacological therapy following the confirmed diagnosis. The study was approved by the local ethics committee (23-11500-BO). Results After screening of 194 consecutive patients, 154 were included in the analysis, while 40 patients were excluded due to insufficient records. The results of this study reveal that a median of 300 (113-962) days elapsed from the initial suspicion of amyloidosis to the final confirmation. Initial indications of CA often presented as nonspecific symptoms such as unclear dyspnea (16.2% n=25), abnormal echocardiography (75.3% n=116), or, in rare cases, incidental findings (8.4% n=13). Following the diagnosis, an additional median of 84 (46-163.5) days passed before the first prescription of a transthyretin stabilizer. To assess an improvement of ATTR-CM diagnosis over time, we stratified the data into tertiles by date of first diagnosis. The results showed a gradually decrease in medium time to diagnosis of 466 (181-1035) days in the earliest tertile (2018-2019) to 389 (141-1508) days in the most recent tertile (2022-2023) (p<0.001). Conclusion This study shows a major healthcare deficit and underscores the medical need for improved screening procedures and diagnostic modalities to expedite the timely diagnosis of CA, as early identification of the condition is crucial for enhancing the quality of life for patients and preventing life-threatening complications.

A Hydroxyquinoline Polymer with Excellent Amyloidosis Inhibition and Protein Delivery Ability to Combat Amyloid-β-Mediated Neurotoxicity.

The accumulation of abnormal protein deposits known as amyloid-β (Aβ) plaques contributes to the development and progression of Alzheimer's disease. Aggregated Aβ exacerbates oxidative stress by stimulating the production of reactive oxygen species (ROS) in a detrimental feedback loop. 8-Hydroxyquinoline (8-HQ) is recognized for its ability to inhibit or reverse Aβ aggregation and reduce neurotoxicity. Here, an 8-HQ-based polymer, DHQ, was developed to combat Aβ-mediated neurotoxicity by delivering an antioxidant enzyme. DHQ efficiently delivers superoxide dismutase into targeted cells, thereby downregulating the intracellular ROS level. Additionally, the polymer effectively inhibits the fibrillization of three proteins involved in fibrosis, β-lactoglobulin (BLG), insulin, and Aβ1-40, at nanomolar concentrations. Cell culture models demonstrated that DHQ reduces ROS levels induced by Aβ1-40 aggregation, rescuing cell viability and preventing apoptosis. Intracellular delivery of SOD further enhanced the ability to maintain the ROS homeostasis. This polymer offers a multifaceted approach to treating diseases associated with amyloidosis.

Blood diagnostic and prognostic biomarkers in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis is a devastating neurodegenerative disease for which the current treatment approaches remain severely limited. The principal pathological alterations of the disease include the selective degeneration of motor neurons in the brain, brainstem, and spinal cord, as well as abnormal protein deposition in the cytoplasm of neurons and glial cells. The biological markers under extensive scrutiny are predominantly located in the cerebrospinal fluid, blood, and even urine. Among these biomarkers, neurofilament proteins and glial fibrillary acidic protein most accurately reflect the pathologic changes in the central nervous system, while creatinine and creatine kinase mainly indicate pathological alterations in the peripheral nerves and muscles. Neurofilament light chain levels serve as an indicator of neuronal axonal injury that remain stable throughout disease progression and are a promising diagnostic and prognostic biomarker with high specificity and sensitivity. However, there are challenges in using neurofilament light chain to differentiate amyotrophic lateral sclerosis from other central nervous system diseases with axonal injury. Glial fibrillary acidic protein predominantly reflects the degree of neuronal demyelination and is linked to non-motor symptoms of amyotrophic lateral sclerosis such as cognitive impairment, oxygen saturation, and the glomerular filtration rate. TAR DNA-binding protein 43, a pathological protein associated with amyotrophic lateral sclerosis, is emerging as a promising biomarker, particularly with advancements in exosome-related research. Evidence is currently lacking for the value of creatinine and creatine kinase as diagnostic markers; however, they show potential in predicting disease prognosis. Despite the vigorous progress made in the identification of amyotrophic lateral sclerosis biomarkers in recent years, the quest for definitive diagnostic and prognostic biomarkers remains a formidable challenge. This review summarizes the latest research achievements concerning blood biomarkers in amyotrophic lateral sclerosis that can provide a more direct basis for the differential diagnosis and prognostic assessment of the disease beyond a reliance on clinical manifestations and electromyography findings.

Dopaminergic neurodegeneration in Gerstmann-Sträussler-Scheinker (P102L) disease: insights from imaging and pathological examination.

Gerstmann-Sträussler-Scheinker (GSS) disease is an inherited prion disease characterized by dementia, cerebellar ataxia, and painful sensory disturbances. GSS is pathologically defined by the presence of amyloid plaques comprised of prion protein predominantly localized in the cerebral cortex, cerebellar cortex, and basal ganglia, resulting from mutations in the prion protein gene. This study investigated five cases of GSS P102L [GSS caused by a leucine (L) substitution of proline (P) at position 102 of the prion protein gene] with L-dopa-resistant extrapyramidal symptoms and reduced dopamine transporter single-photon emission computed tomography (DAT-SPECT) uptake. Clinical findings revealed diverse manifestations, with all cases exhibiting parkinsonism, and four patients had a vertical gaze palsy. Notably, all patients showed reduced striatal DAT-SPECT uptake, indicating neurodegeneration of the nigrostriatal system. Autopsy findings in one case confirmed prion protein plaques and dopaminergic neuron loss in the substantia nigra of a patient with GSS P102L. Additionally, reduced DAT immunostaining was observed in the putamen compared with a control. While previous studies have identified reduced DAT-SPECT and positron emission tomography uptake in Creutzfeldt-Jakob disease and fatal familial insomnia owing to nigrostriatal neurodegeneration induced by abnormal prion protein deposition, similar phenomena in GSS P102L have not been reported. This study provides support for a correlation between abnormal prion protein deposition and nigrostriatal system degeneration in GSS P102L. Our results reveal the importance of considering GSS P102L in cases of atypical Parkinsonism and abnormal DAT-SPECT results, which would serve as a valuable indicator for subsequent prion genetic testing.

Challenges in the approach to a patient with aortic stenosis and cardiac amyloidosis with ATTR mutation associated with negative scintigraphy - A case report

IntroductionCardiac amyloidosis (CA) poses significant diagnostic and therapeutic challenges. In this case report, we detail a patient with CA due to a rare transthyretin (CA-TTR) mutation, manifesting with negative myocardial scintigraphy and requiring genetic testing for diagnosis. The patient also had severe aortic stenosis (AS), necessitating discussion with a heart team to determine the optimal treatment strategy. Case reportA 70-year-old male with a family history of sudden death was previously diagnosed with third-degree atrioventricular block and treated with a pacemaker. He presented with worsening exertional dyspnoea, and examination revealed a third heart sound, a systolic murmur indicative of AS and bilateral muscular atrophy in the thenar region. Transthoracic echocardiography indicated severe AS and moderate left ventricular dysfunction, with images suggesting infiltrative disease. Pyrophosphate scintigraphy revealed no abnormal cardiac tracer uptake. Cardiac magnetic resonance imaging (MRI) revealed extensive, heterogeneous, subendocardial late gadolinium enhancement in both the atria and ventricles, which was consistent with CA. Genetic testing identified the Phe84Leu mutation in the TTR gene. Following heart team discussions, the patient underwent successful transcatheter aortic valve implantation (TAVI) and remained asymptomatic in follow-up, being monitored at an outpatient clinic specializing in CA and using tafamidis. DiscussionCA-TTR can be an autosomal dominant disease with variable penetrance involving abnormal amyloid protein deposition in tissues and can often be diagnosed noninvasively via myocardial scintigraphy. However, some TTR mutations do not affect scintigraphy results, necessitating genetic testing when clinical suspicion is high, potentially avoiding endomyocardial biopsy. Moreover, AS occurs in up to 16 % of TTR amyloidosis patients, with the conditions mutually exacerbating each other. Recent consensus suggests that TAVI reduces mortality in patients with severe AS and amyloidosis. ConclusionsVarious diagnostic algorithms emphasize the use of myocardial scintigraphy for suspected CA-TTR. Genetic testing is crucial when scintigraphy results are negative, but clinical suspicion remains high, potentially circumventing invasive procedures. Compared with medical management alone, TAVI has been shown to improve quality of life and survival in patients with concurrent severe AS and CA.

Enhancing Classification of Alzheimer’s Disease using Spatial Attention Mechanism

Aim This study aims to enhance the precision of Alzheimer's disease (AD) detection by integrating Spatial Attention Mechanism into a Convolutional Neural Network (CNN) architecture. Background Alzheimer's disease is a progressive neurodegenerative disorder characterized by abnormal protein deposits in the brain, leading to nerve cell loss and posing a significant global health challenge. Early and accurate detection is crucial for disease management and treatment due to the lack of a cure and the disease's severe progression. Objective The objective of this research is to improve the accuracy of Alzheimer's disease classification using MRI data by implementing a Spatial Attention Mechanism in a CNN architecture. Methods The study utilized T1-weighted MRI data from the OASIS 1 and OASIS 2 datasets. The key innovation is the Spatial Attention layer incorporated within a CNN model, which computes the average of each channel in the input feature map. This layer guides subsequent layers to focus on critical brain regions, enhancing the model's accuracy in differentiating between Alzheimer's disease stages. Results The model achieved a validation accuracy of 99.69% with a sensitivity and specificity of 1.0000, demonstrating its reliability in distinguishing between different stages of Alzheimer's disease. The adaptability of the Spatial Attention layer allows the model to assign higher weights to crucial brain regions, improving its discriminative power. Conclusion The integration of the Spatial Attention Mechanism into the CNN architecture significantly contributes to the early detection of Alzheimer's disease, enabling timely interventions. This innovative approach has the potential to revolutionize Alzheimer's diagnosis by enhancing accuracy and offering a robust solution for classification.

A Case Report on Renal Amyloidosis

Amyloidosis involves the deposition of abnormal proteins in various tissue and result in progressive organ dysfunction, commonly affecting multiple organs. Two types of systemic amyloidosis are AA and AL, the former is associated with acute phase reaction and the later is composed of light chain immunoglobulin. This disease commonly affects the kidneys and is evidenced by massive proteinuria. A biopsy is the gold standard of diagnosis, with Congo Red staining revealing an apple green birefringence under polarized light microscope. We are presenting a 45 years old male who presented with rapid rising serum creatinine with history of multiple myeloma (non secretory). There was also history of spine tuberculosis.

Inhibition of tartrate-resistant acid phosphatase 5 can prevent cardiac fibrosis after myocardial infarction

BackgroundMyocardial infarction (MI) leads to enhanced activity of cardiac fibroblasts (CFs) and abnormal deposition of extracellular matrix proteins, resulting in cardiac fibrosis. Tartrate-resistant acid phosphatase 5 (ACP5) has been shown to promote cell proliferation and phenotypic transition. However, it remains unclear whether ACP5 is involved in the development of cardiac fibrosis after MI. The present study aimed to investigate the role of ACP5 in post-MI fibrosis and its potential underlying mechanisms.MethodsClinical blood samples were collected to detect ACP5 concentration. Myocardial fibrosis was induced by ligation of the left anterior descending coronary artery. The ACP5 inhibitor, AubipyOMe, was administered by intraperitoneal injection. Cardiac function and morphological changes were observed on Day 28 after injury. Cardiac CFs from neonatal mice were extracted to elucidate the underlying mechanism in vitro. The expression of ACP5 was silenced by small interfering RNA (siRNA) and overexpressed by adeno-associated viruses to evaluate its effect on CF activation.ResultsThe expression of ACP5 was increased in patients with MI, mice with MI, and mice with Ang II-induced fibrosis in vitro. AubipyOMe inhibited cardiac fibrosis and improved cardiac function in mice after MI. ACP5 inhibition reduced cell proliferation, migration, and phenotypic changes in CFs in vitro, while adenovirus-mediated ACP5 overexpression had the opposite effect. Mechanistically, the classical profibrotic pathway of glycogen synthase kinase-3β (GSK3β)/β-catenin was changed with ACP5 modulation, which indicated that ACP5 had a positive regulatory effect. Furthermore, the inhibitory effect of ACP5 deficiency on the GSK3β/β-catenin pathway was counteracted by an ERK activator, which indicated that ACP5 regulated GSK3β activity through ERK-mediated phosphorylation, thereby affecting β-catenin degradation.ConclusionACP5 may influence the proliferation, migration, and phenotypic transition of CFs, leading to the development of myocardial fibrosis after MI through modulating the ERK/GSK3β/β-catenin signaling pathway.

Stable ubiquitin conjugation for biological interrogation of ubiquitinated tau repeat domain

Protein semisynthesis approaches are key for gaining insights into the effects of post-translational modifications (PTMs) on the structure and function of modified proteins. Among PTMs, ubiquitination involves the conjugation of a small protein modifier to a substrate amino acid residue and is unique in controlling a variety of cellular processes. Interest has grown in understanding the role of ubiquitination in neurodegenerative conditions, including tauopathies. The latter are characterized by the accumulation of the intrinsically disordered protein tau in the form of neurofibrillary tangles in the brains of patients. The presence of ubiquitinated tau in the pathological aggregates suggests that ubiquitination might play a role in the formation of abnormal protein deposits. In this study, we developed a new strategy, based on dehydroalanine chemistry, to install wild type ubiquitin on a tau repeat domain construct with site-specificity. We optimized a three-step reaction which yielded a good amount of highly pure tau repeat domain ubiquitinated in position 353. The structural features of the conjugate were examined by circular dichroism and NMR spectroscopy. The ubiquitinated tau was challenged in a number of assays: fibrils formation under aggregating conditions in vitro, chemical stability upon exposure to a variety of biological media including cell extracts, and internalization into astrocytes. The results demonstrated the wide applicability of the new semisynthetic strategy for the investigation of ubiquitinated substrates in vitro or in cell, and in particular for studying if ubiquitination has a role in the molecular mechanisms that underlie the aberrant transition of tau into pathological aggregates.

Anticoagulation in Atrial Fibrillation Associated With Cardiac Amyloidosis: A Narrative Review.

Cardiac amyloidosis (CA) involves the abnormal deposition and accumulation of amyloid proteins in the heart muscle. A hallmark of disease progression is declining heart function, which can lead to structural irregularities, arrhythmias, and ultimately heart failure. Atrial fibrillation (AF) is the most common arrhythmia that presents in CA patients, and this arrhythmia is significant because it can moderately increase the risk of patients developing intracardiac thrombi, thereby putting them at risk for thromboembolic events. The management of this complication entails the use of anticoagulants like vitamin K antagonists and direct oral anticoagulants to reduce the risk of thrombus formation. This article seeks to review AF in CA and the use of anticoagulation therapy for the management and reduction of thromboembolic risk. The major conclusions of this review are centered around the need for safe administration of anticoagulant therapy to CA patients, regardless of their CHA2DS2-VASc risk score. This review highlights the importance of taking a multidisciplinary or collaborative approach to CA treatment to ensure that all aspects of this multifaceted disease can be properly managed while minimizing adverse events like bleeding risk and drug-drug interactions.

A Rare Case of Cardiac Amyloidosis Secondary to Multiple Myeloma in A Young Male Presenting with Shortness of Breath

Introduction: Multiple myeloma (MM) is a haematological malignancy associated with various systemic manifestations, including AL amyloidosis.AL amyloidosis is a systemic condition arising from abnormal protein misfolding and deposition, leading to organ dysfunction. Cardiorenal involvement is characteristic. Cardiac amyloidosis causes significant morbidity and mortality, particularly in MM patients. Case Report: A 40-year-old previously well male presented with exertional dyspnoea, lower limb swelling, and frothy urine. Clinical examination and investigations were consistent with an MM complicated by AL amyloidosis affecting the heart and kidneys. The diagnosis of amyloidosis was confirmed through renal biopsies revealing Congo red positivity, along with cardiac imaging showing typical amyloidosis findings. The presence of bone marrow plasma cells 72% confirmed myeloma. Conclusion: This case highlights the challenges in managing MM-associated AL amyloidosis with cardiac and renal involvement. It underscores the importance of comprehensive diagnostic approaches, multidisciplinary collaboration, and tailored treatment strategies. Despite the poor prognosis, diligent management can lead to favourable outcomes and improved quality of life for affected individuals.

Management of Arrhythmias and Conduction Disorders in Amyloid Cardiomyopathy.

Cardiac amyloidosis, a condition characterized by abnormal protein deposition in the heart, leads to restrictive cardiomyopathy and is notably associated with an increased risk of arrhythmias and conduction disorders. This article reviews the current understanding and management strategies for these cardiac complications, with a focus on recent advancements and clinical challenges. The prevalence and impact of atrial arrhythmias, particularly atrial fibrillation, are examined, along with considerations for stroke risk and anticoagulation therapy. The article also addresses the complexities of managing rate and rhythm control, outlining the utility and limitations of pharmacological agents and interventions such as catheter ablation. Furthermore, it reviews the challenges in the treatment of ventricular arrhythmias, including the contentious use of implantable cardioverter-defibrillators for primary and secondary prevention. Individualized approaches, considering the unique characteristics of cardiac amyloidosis, are paramount. Continuous research and clinical exploration are essential to refine treatment strategies and improve outcomes in this challenging patient population.

Misfolded protein deposits in Parkinson’s disease and Parkinson’s disease-related cognitive impairment, a [11C]PBB3 study

Parkinson’s disease (PD) is associated with aggregation of misfolded α-synuclein and other proteins, including tau. We designed a cross-sectional study to quantify the brain binding of [11C]PBB3 (a ligand known to bind to misfolded tau and possibly α-synuclein) as a proxy of misfolded protein aggregation in Parkinson’s disease (PD) subjects with and without cognitive impairment and healthy controls (HC). In this cross-sectional study, nineteen cognitively normal PD subjects (CN-PD), thirteen cognitively impaired PD subjects (CI-PD) and ten HC underwent [11C]PBB3 PET. A subset of the PD subjects also underwent PET imaging with [11C](+)DTBZ to assess dopaminergic denervation and [11C]PBR28 to assess neuroinflammation. Compared to HC, PD subjects showed higher [11C]PBB3 binding in the posterior putamen but not the substantia nigra. There was no relationship across subjects between [11C]PBB3 and [11C]PBR28 binding in nigrostriatal regions. [11C]PBB3 binding was increased in the anterior cingulate in CI-PD compared to CN-PD and HC, and there was an inverse correlation between cognitive scores and [11C]PBB3 binding in this region across all PD subjects. Our results support a primary role of abnormal protein deposition localized to the posterior putamen in PD. This suggests that striatal axonal terminals are preferentially involved in the pathophysiology of PD. Furthermore, our findings suggest that anterior cingulate pathology might represent a significant in vivo marker of cognitive impairment in PD, in agreement with previous neuropathological studies.

Sleep disturbance in clinical and preclinical scrapie-infected sheep measured by polysomnography

Neurodegenerative diseases are characterised by neuronal loss and abnormal deposition of pathological proteins in the nervous system. Among the most common neurodegenerative diseases are Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease and transmissible spongiform encephalopathies (TSEs). Sleep and circadian rhythm disturbances are one of the most common symptoms in patients with neurodegenerative diseases. Currently, one of the main objectives in the study of TSEs is to try to establish an early diagnosis, as clinical signs do not appear until the damage to the central nervous system is very advanced, which prevents any therapeutic approach. In this paper, we provide the first description of sleep disturbance caused by classical scrapie in clinical and preclinical sheep using polysomnography compared to healthy controls. Fifteen sheep classified into three groups, clinical, preclinical and negative control, were analysed. The results show a decrease in total sleep time as the disease progresses, with significant changes between control, clinical and pre-clinical animals. The results also show an increase in sleep fragmentation in clinical animals compared to preclinical and control animals. In addition, sheep with clinical scrapie show a total loss of Rapid Eye Movement sleep (REM) and alterations in Non Rapid Eyes Movement sleep (NREM) compared to control sheep, demonstrating more shallow sleep. Although further research is needed, these results suggest that prion diseases also produce sleep disturbances in animals and that polysomnography could be a diagnostic tool of interest in clinical and preclinical cases of prion diseases.

The role of the Pin1-cis P-tau axis in the development and treatment of vascular contribution to cognitive impairment and dementia and preeclampsia.

Tauopathies are neurodegenerative diseases characterized by deposits of abnormal Tau protein in the brain. Conventional tauopathies are often defined by a limited number of Tau epitopes, notably neurofibrillary tangles, but emerging evidence suggests structural heterogeneity among tauopathies. The prolyl isomerase Pin1 isomerizes cis P-tau to inhibit the development of oligomers, tangles and neurodegeneration in multiple neurodegenerative diseases such as Alzheimer's disease, traumatic brain injury, vascular contribution to cognitive impairment and dementia (VCID) and preeclampsia (PE). Thus, cis P-tau has emerged as an early etiological driver, blood marker and therapeutic target for multiple neurodegenerative diseases, with clinical trials ongoing. The discovery of cis P-tau and other tau pathologies in VCID and PE calls attention for simplistic classification of tauopathy in neurodegenerative diseases. These recent advances have revealed the exciting novel role of the Pin1-cis P-tau axis in the development and treatment of vascular contribution to cognitive impairment and dementia and preeclampsia.

Diagnostic problems of rare diseases - amyloidosis. A case report

The presented case study focuses on the complexities and challenges in diagnosingone of the forms of amyloidosis, where abnormal protein (amyloid) deposits in variousorgans and tissues lead to affection of many organs, especially the heart, kidneys, liver,spleen, and occasionally the central nervous system. Its aetiology remains largely unknown,making diagnosis and treatment particularly challenging.This report details the case of an 88-year-old patient, disabled for months (with amodified Rankin Scale score of 4), who presented to the Neurology Department with suddenright limb paresis and speech disorders. Initial assessments indicated suggested ischemicstroke, and patients received thrombolysis. Further laboratory tests and imaging, includingserum protein electrophoresis and computer tomograph (CT) scans, suggested transthyretinamyloidosis (ATTR), which was later confirmed through genetic testing.This case underscores the rapid, multi-organ progression of amyloidosis and itsdevastating impact, highlighting the necessity for early diagnosis and a multidisciplinarytreatment approach.Despite ongoing research, the pathogenesis of amyloidosis remains elusive, andcurrent treatment options are primarily symptomatic. This study aims to shed light on thediagnostic difficulties and the urgent need for timely intervention in amyloidosis cases.

A case of bilateral amyloidosis localized to extraocular muscles mimicking thyroid eye disease

BackgroundAmyloidosis is a rare condition characterized by the abnormal deposition of amyloid proteins in various tissues and organs. While systemic amyloidosis has been well-documented, amyloid deposition in extraocular muscles is an exceptionally rare occurrence, with only 35 reported cases. This case report sheds light on the importance of considering amyloidosis in the differential diagnosis of patients presenting with proptosis and diplopia, which are often associated with thyroid eye disease.Case presentationA woman in her twenties sought medical attention due to a complaint of diplopia. Her ocular examination revealed almost normal findings except for exotropia and proptosis. Orbital magnetic resonance imaging displayed fusiform enlargement of nearly all eye muscles, a presentation typically observed in thyroid eye disease. However, despite corticosteroid therapy, her symptoms showed no improvement. Given the unusual lack of response to conventional treatment, and inhomogeneous enhancement of the muscle, an extraocular muscle biopsy was conducted. This biopsy yielded a unique finding—amyloid deposition within the muscle tissue. This discovery was particularly intriguing due to the extreme rarity of amyloidosis affecting extraocular muscles, with fewer than three dozen documented cases worldwide.ConclusionThis unique case underscores the critical need for a comprehensive approach to diagnosing patients with proptosis and diplopia. While these symptoms are commonly attributed to thyroid eye disease, it is essential to consider alternative diagnoses such as amyloidosis, especially when standard treatments fail to yield results. The discovery of amyloid deposition in the extraocular muscles, although exceedingly rare, emphasizes the significance of a thorough differential diagnosis. In conclusion, this case report highlights the importance of vigilance in clinical practice, encouraging ophthalmologists to explore less common diagnostic possibilities when faced with challenging cases. Further research and clinical investigation are warranted to better understand the mechanisms and potential treatments for amyloidosis affecting the extraocular muscles.

Molecular basis for non-invasive diagnostics of cardiac amyloids using bone tracers.

Amyloid diseases including Alzheimer's, Parkinson's and over 30 others are incurable life-threatening disorders caused by abnormal protein deposition as fibrils in various organs. Cardiac amyloidosis is particularly challenging to diagnose and treat. Identification of the fibril-forming protein, which in the heart is usually amyloid transthyretin (ATTR) or amyloid immunoglobulin light chain (AL), is paramount to treatment. A transformative non-invasive diagnostic modality is imaging using technetium-labeled pyrophosphate or diphosphonate bone tracers, 99mTc-PYP/DPD/HMDP. For unknown reasons, these tracers show preferential uptake by ATTR deposits. The tracer-binding moiety is unknown and potentially involves amyloid fibrils and/or amyloid-associated calcific deposits. We propose that, like in the bone, the tracers chelate to surface-bound Ca2+ in amyloid. In high-affinity protein sites, Ca2+ is coordinated by pairs of acidic residues. To identify such residues on amyloids, we harnessed atomic structures of patient-derived cardiac amyloids determined using cryogenic electron microscopy since 2019. These structures help explain why most but not all ATTR deposits uptake 99mTc-PYP/DPD/HMDP radiotracers, while in AL the opposite is true. Moreover, fibril structures help explain greater microcalcification observed in ATTR vs. AL deposits. These findings may aid the diagnostics and therapeutic targeting of cardiac amyloidosis and are relevant to other amyloids.

The alteration and role of glycoconjugates in Alzheimer's disease.

Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by abnormal protein deposition. With an alarming 30 million people affected worldwide, AD poses a significant public health concern. While inhibiting key enzymes such as β-site amyloid precursor protein-cleaving enzyme 1 and γ-secretase or enhancing amyloid-β clearance, has been considered the reasonable strategy for AD treatment, their efficacy has been compromised by ineffectiveness. Furthermore, our understanding of AD pathogenesis remains incomplete. Normal aging is associated with a decline in glucose uptake in the brain, a process exacerbated in patients with AD, leading to significant impairment of a critical post-translational modification: glycosylation. Glycosylation, a finely regulated mechanism of intracellular secondary protein processing, plays a pivotal role in regulating essential functions such as synaptogenesis, neurogenesis, axon guidance, as well as learning and memory within the central nervous system. Advanced glycomic analysis has unveiled that abnormal glycosylation of key AD-related proteins closely correlates with the onset and progression of the disease. In this context, we aimed to delve into the intricate role and underlying mechanisms of glycosylation in the etiopathology and pathogenesis of AD. By highlighting the potential of targeting glycosylation as a promising and alternative therapeutic avenue for managing AD, we strive to contribute to the advancement of treatment strategies for this debilitating condition.

Avaliação Cintilográfica e Ecocardiográfica em Portadores de Variantes Patogênicas ou Provavelmente Patogênicas do Gene TTR sem Envolvimento Cardíaco Manifesto

Abstract Background: Transthyretin amyloidosis (ATTR) is an infiltrative disease caused by abnormal protein deposition mainly in the heart and peripheral nervous system. When it affects the heart, the disease presents as restrictive cardiomyopathy; when it affects the peripheral and autonomic nervous system, it manifests as polyneuropathy, and is called familial amyloid polyneuropathy (FAP). There are two ATTR subtypes: wild-type ATTR, where there is no mutation, and mutant ATTR (ATTRm), which is characterized by a mutation in the gene encoding the transthyretin protein (TTR). In both subtypes, cardiac involvement is the major marker of poor prognosis. Objectives: To assess the prevalence of subclinical cardiac involvement in a sample of patients with TTR gene mutation by using pyrophosphate scintigraphy and strain echocardiography; to compare scintigraphy and strain findings; to evaluate the association between neurological manifestations (FAP) and subclinical cardiac involvement; and to analyze whether there is an association between any specific mutation and cardiac involvement. Methods: This is a cross-sectional study with carriers of the TTR gene mutation, without cardiovascular symptoms or changes in electrocardiographic or conventional echocardiographic parameters. All patients underwent pyrophosphate scintigraphy and strain echocardiography. Subclinical cardiac involvement was defined as a Perugini score ≥ 2, heart-to-contralateral lung (H/CL) ratio ≥ 1.5 at 1 h, H/CL ≥1.3 at 3 h, or global longitudinal strain (GLS) ≤ −17%. Descriptive and analytical analyses were performed and Fisher's exact test and Mann–Whitney test were applied. A value of p < 0.05 was considered significant. Results: The 23 patients evaluated had a median age of 51 years (IQR 37–57 years), 15 (65.2%) were female, 12 (52.2%) were Pardo, nine (39.1%) had systemic arterial hypertension, and nine (39.1%) had a previous diagnosis of FAP. Of the nine patients with FAP, 8 (34.8%) were on tafamidis. The associated mutations were Val142IIe, Val50Met, and IIe127Val. The median GLS in the sample was −19% (−16% to −20%). Of the 23 patients, nine (39.1%; 95% CI = 29–49%) met criteria for cardiac involvement, six (26%) by the GLS-based criteria only. There was no association between having FAP and being an asymptomatic carrier, as assessed by strain echocardiography and pyrophosphate scintigraphy (p = 0.19). The prevalence of systemic arterial hypertension, diabetes mellitus, dyslipidemia, smoking, and reduced GLS did not differ between groups. Septal e’ wave velocity was the only variable that significantly differed between individuals with and without reduced GLS, with an area under the ROC curve of 0.80 (95% CI = 0.61–0.98, p = 0.027). The best diagnostic accuracy was achieved with a septal e’ velocity ≤ 8.5 cm/s. There was no association between mutation type and preclinical cardiac involvement, nor between tafamidis use and lower degree of cardiac involvement (37.5% versus 40.0%, p = 0.90). Conclusion: Subclinical cardiac involvement was common in a sample of TTR mutation carriers without cardiac involvement. Reduced left ventricular GLS was the most frequent finding. There was no association between the presence of amyloid polyneuropathy and subclinical cardiac involvement. Type of mutation was not associated with early cardiac involvement. In this sample, the use of tafamidis 20 mg/day was not associated with a lower prevalence of subclinical cardiac involvement.