Sex-Related Risk of Cardiac Involvement in Hereditary Transthyretin Amyloidosis: Insights From THAOS

Objectives: Because patients with ATTRv cardiomyopathy are more likely to be male, this analysis aimed to increase information on associations between sex and genotype, phenotype, and degree of myocardial involvement in ATTRv amyloidosis. Background: Transthyretin amyloid cardiomyopathy is a progressive, fatal disease that occurs due to accumulation of wild-type or variant (ATTRv) transthyretin amyloid fibrils in the myocardium. Methods: The Transthyretin Amyloidosis Outcomes Survey (THAOS) is an ongoing global longitudinal observational survey of patients with ATTR amyloidosis and asymptomatic carriers with TTR mutations. Data from THAOS (data cutoff: January 6, 2020) were analyzed to determine any sex-based differences in genotype, phenotype, and presence of cardiac and neurological symptoms in patients with ATTRv amyloidosis and in patients with ATTRv amyloidosis and cardiomyopathy. Results: There were 2,790 patients with ATTRv amyloidosis enrolled in THAOS, with male patients more likely to have symptoms of cardiac involvement and a cardiac phenotype. Male prevalence was greater in patients with more severe cardiac manifestations of disease, as assessed with N-terminal pro–B-type natriuretic peptide, left-ventricular (LV) ejection fraction, mean LV wall thickness divided by height, and LV mass index divided by height. Sex, age at disease onset, and genotype category were identified by multivariate analyses as risk factors for the development of cardiomyopathy (defined as increased LV septum thickness divided by height). Conclusions: In this analysis, myocardial involvement was more frequent and pronounced in male patients with ATTRv amyloidosis, suggesting that there may be biological characteristics that inhibit myocardial amyloid infiltration in females or facilitate it in males

Serum neurofilament light chain: a promising early diagnostic biomarker for hereditary transthyretin amyloidosis?

Background and purpose: Hereditary transthyretin amyloidosis (ATTRv) is a life-threatening disease caused by mutations in the gene encoding transthyretin (TTR). The recent therapeutic advances have underlined the importance of easily accessible, objective biomarkers of both disease onset and progression. Preliminary evidence suggests a potential role in this respect for neurofilament light chain (NfL). In this study, the aim was to determine serum NfL (sNfL) levels in a late-onset ATTRv population and evaluate whether it might represent a reliable biomarker of disease onset (i.e., ' conversion ' from the asymptomatic status to symptomatic disease in TTR mutation carriers).Methods: In all, 111 individuals harbouring a pathogenic TTR variant (61 symptomatic ATTRv patients and 50 presymptomatic carriers) were consecutively enrolled. Fifty healthy volunteers were included as the control group. EllaT apparatus was used to assess sNfL levels.Results: Serum NfL levels were increased in ATTRv patients compared to both presymptomatic carriers and healthy controls, whilst not differing between carriers and healthy controls. An sNfL cut-off of 37.10 pg/mL could discriminate between asymptomatic and symptomatic individuals with high diagnostic accuracy (area under the curve 0.958; p < 0.001), sensitivity (81.4%) and specificity (100%).Conclusions: Serum NfL seems to be a promising biomarker of peripheral nerve involvement in ATTRv amyloidosis and might become a reliable, objective measure to detect the transition from the presymptomatic stage to the onset of symptomatic disease. Further longitudinal studies are needed to confirm such a role and determine whether it could equally represent a biomarker of disease progression and response to therapy

PERIPHERAL NERVOUS SYSTEM INVOLVEMENT IN LYMPHOPROLIFERATIVE DISORDERS

Peripheral neuropathies are a vast group of diseases with heterogeneous aetiologies, including genetic and acquired causes. Several haematological disorders may cause an impairment of the peripheral nervous system, with diverse mechanisms and variable clinical, electrophysiological and pathological manifestations. In this practical review we considered the main phenotypes of peripheral nervous diseases and examined the haematological disorders which may associate with each of them. The area of intersection of neurological and haematological fields is of particular complexity and raises several problems in clinical practice. The personal crosstalk between neurologists and haematologists remains a fundamental tool for  a proper diagnostic process  which  may lead to successful treatments in  most cases

Current Evidence Supporting the Role of Immune Response in ATTRv Amyloidosis

Hereditary transthyretin (ATTRv) amyloidosis with polyneuropathy, also known as familial amyloid polyneuropathy (FAP), represents a progressive, heterogeneous, severe, and multisystemic disease caused by pathogenic variants in the TTR gene. This autosomal-dominant neurogenetic disorder has an adult onset with variable penetrance and an inconstant phenotype, even among subjects carrying the same mutation. Historically, ATTRv amyloidosis has been viewed as a non-inflammatory disease, mainly due to the absence of any mononuclear cell infiltration in ex vivo tissues; nevertheless, a role of inflammation in its pathogenesis has been recently highlighted. The immune response may be involved in the development and progression of the disease. Fibrillary TTR species bind to the receptor for advanced glycation end products (RAGE), probably activating the nuclear factor κB (NF-κB) pathway. Moreover, peripheral blood levels of several cytokines, including interferon (IFN)-gamma, IFN-alpha, IL-6, IL-7, and IL-33, are altered in the course of the disease. This review summarizes the current evidence supporting the role of the immune response in ATTRv amyloidosis, from the pathological mechanisms to the possible therapeutic implications

Peripherin, a new promising biomarker in neurological disorders

: Peripherin is a class III intermediate filament protein that has recently gained attention as a potential biomarker for axonal damage in the peripheral nervous system. This review examines peripherin gene expression, protein structure, and its functions in both healthy and diseased states. Peripherin is predominantly expressed in the peripheral nervous system, especially in motor and sensory neurons, and plays a critical role in neurite growth, stability, and axonal transport during myelination. Its expression is regulated by various cytokines and undergoes several post-transcriptional modifications. Peripherin interacts with multiple proteins, including neurofilaments and kinases, influencing cytoskeletal dynamics and neuronal functions. The review also explores peripherin involvement in several neurological disorders, such as Amyotrophic Lateral Sclerosis, where its abnormal expression and aggregation contribute to disease pathology. Additionally, peripherin has been linked to polyneuropathies, traumatic axonal injury, and diabetic neuropathy, suggesting its broader relevance as a biomarker in these conditions. The potential of peripherin as a biomarker is further supported by recent studies using ultrasensitive detection methods, which have identified elevated peripherin levels in the serum of patients with neurological diseases. Despite the promising findings, the application of peripherin as a biomarker in clinical settings remains limited, primarily due to challenges in its detection and the need for further validation in diverse patient populations. Future research directions include the development of more sensitive assays and the exploration of peripherin's role in non-neuronal tissues, which may expand its diagnostic and therapeutic potential

Neurofilament Light Chains in Systemic Amyloidosis:A Systematic Review

Peripheral and autonomic neuropathy are common disease manifestations in systemic amyloidosis. The neurofilament light chain (NfL), a neuron-specific biomarker, is released into the blood and cerebrospinal fluid after neuronal damage. There is a need for an early and sensitive blood biomarker for polyneuropathy, and this systematic review provides an overview on the value of NfL in the early detection of neuropathy, central nervous system involvement, the monitoring of neuropathy progression, and treatment effects in systemic amyloidosis. A literature search in PubMed, Embase, and Web of Science was performed on 14 February 2024 for studies investigating NfL levels in patients with systemic amyloidosis and transthyretin gene-variant (TTRv) carriers. Only studies containing original data were included. Included were thirteen full-text articles and five abstracts describing 1604 participants: 298 controls and 1306 TTRv carriers or patients with or without polyneuropathy. Patients with polyneuropathy demonstrated higher NfL levels compared to healthy controls and asymptomatic carriers. Disease onset was marked by rising NfL levels. Following the initiation of transthyretin gene-silencer treatment, NfL levels decreased and remained stable over an extended period. NfL is not an outcome biomarker, but an early and sensitive disease-process biomarker for neuropathy in systemic amyloidosis. Therefore, NfL has the potential to be used for the early detection of neuropathy, monitoring treatment effects, and monitoring disease progression in patients with systemic amyloidosis.</p

Generation of an induced pluripotent stem cell line (UCSCi002-A) from a patient with a variant in TARDBP gene associated with familial amyotrophic lateral sclerosis and frontotemporal dementia

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that selectively affects motor neurons. In 20% of cases, ALS appears in comorbidity with frontotemporal dementia (FTD). We generated patient-derived-induced Pluripotent Stem Cells (iPSCs), from an ALS/FTD patient. The patient had a familial form of the disease and a missense variant in TARDBP gene. We used an established protocol based on Sendai virus to reprogram fibroblasts. We confirmed the stemness and the pluripotency of the iPSC clones, thus generating embryoid bodies. We believe that the iPSC line carrying a TARDBP mutation could be a valuable tool to investigate TDP-43 proteinopathy linked to ALS

Tetrameric Transthyretin as a Protective Factor Against Alzheimer’s Disease

: Transthyretin (TTR) is a tetrameric protein traditionally recognized for its role in transporting thyroxine and retinol. Recent research has highlighted the potential neuroprotective functions of TTR in the setting of Alzheimer's disease (AD), which is the most common form of dementia and is caused by the deposition of amyloid beta (Aβ) and the resulting cytotoxic effects. This paper explores the mechanisms of TTR protective action, including its interaction with Aβ to prevent fibril formation and promote Aβ clearance from the brain. It also synthesizes experimental evidence suggesting that enhanced TTR stability may mitigate neurodegeneration and cognitive decline in AD. Potential therapeutic strategies such as small molecule stabilizers of TTR are discussed, highlighting their role in enhancing TTR binding to Aβ and facilitating its clearance. By consolidating current knowledge and proposing directions for future research, this review aims to underscore the significance of TTR as a neuroprotective factor in AD and the potential implications for future research

Serum Neurofilament and Free Light Chain Levels in Patients Undergoing Treatment for Chronic Inflammatory Demyelinating Polyneuropathy

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an immune-mediated disorder affecting the peripheral nervous system. Despite the established diagnostic criteria, monitoring disease activity and treatment remains challenging. To address this limitation, we investigated serum neurofilament light chain (sNfL) and serum free light chains (sFLCs) as potential biomarkers. A total of 32 CIDP patients undergoing immunoglobulin therapy and 32 healthy controls enrolled in the present study, and agreed to have their blood plasma sNfL and sFLCs analyzed, while CIDP severity was assessed through the modified Rankin Scale (mRS) and the Overall Neuropathy Limitations Scale (ONLS). In line with the immunoglobulin treatment aimed at limiting neuronal damage administered to the majority of patients, sNfL levels did not exhibit significant differences between the two groups. However, CIDP patients showed significantly elevated sFLC and sFLC ratios, while the marker levels did not correlate with the clinical scores. The study confirms the potential of sFLCs as a sensitive biomarker of inflammatory processes in CIDP. Additionally, the present study results regarding neurofilaments strengthen the role of sNfL in monitoring CIDP treatments, confirming the effectiveness of immunoglobulin therapy. Overall, our results demonstrate how combining these markers can lead to better patient characterization for improved treatment

Serum neurofilament light chain: a promising early diagnostic biomarker for hereditary transthyretin amyloidosis?

Background and purpose: Hereditary transthyretin amyloidosis (ATTRv) is a life-threatening disease caused by mutations in the gene encoding transthyretin (TTR). The recent therapeutic advances have underlined the importance of easily accessible, objective biomarkers of both disease onset and progression. Preliminary evidence suggests a potential role in this respect for neurofilament light chain (NfL). In this study, the aim was to determine serum NfL (sNfL) levels in a late-onset ATTRv population and evaluate whether it might represent a reliable biomarker of disease onset (i.e., 'conversion' from the asymptomatic status to symptomatic disease in TTR mutation carriers). Methods: In all, 111 individuals harbouring a pathogenic TTR variant (61 symptomatic ATTRv patients and 50 presymptomatic carriers) were consecutively enrolled. Fifty healthy volunteers were included as the control group. Ella™ apparatus was used to assess sNfL levels. Results: Serum NfL levels were increased in ATTRv patients compared to both presymptomatic carriers and healthy controls, whilst not differing between carriers and healthy controls. An sNfL cut-off of 37.10 pg/mL could discriminate between asymptomatic and symptomatic individuals with high diagnostic accuracy (area under the curve 0.958; p &lt; 0.001), sensitivity (81.4%) and specificity (100%). Conclusions: Serum NfL seems to be a promising biomarker of peripheral nerve involvement in ATTRv amyloidosis and might become a reliable, objective measure to detect the transition from the presymptomatic stage to the onset of symptomatic disease. Further longitudinal studies are needed to confirm such a role and determine whether it could equally represent a biomarker of disease progression and response to therapy