Systemic amyloidosis can be hereditary or acquired with autosomal dominant mutations in the transthyretin gene (TTR ) being the most common cause of hereditary amyloidosis. ATTRm amyloidosis is a multi-system disorder with cardiovascular, peripheral and autonomic nerve involvement that can be difficult to diagnose due to phenotypic heterogeneity. This review will focus on the neuropathic manifestations of ATTRm, the genotype-phenotype variability, the diagnostic approach and the recent therapeutic advances in this disabling condition.
Hereditary transthyretin amyloidosis (ATTRm) causes a disabling peripheral neuropathy as part of a multisystem disorder. The recent development of highly effective gene silencing therapies has highlighted the need for effective biomarkers of disease activity to guide the decision of when to start and stop treatment. In this study, we measured plasma neurofilament light chain (pNfL) concentration in 73 patients with ATTR and found that pNfL was significantly raised in ATTRm patients with peripheral neuropathy compared to healthy controls. Furthermore, pNFL correlated with disease severity as defined by established clinical outcome measures in patients for whom this information was available. These findings suggest a potential role of pNfL in monitoring disease activity and progression in ATTRm patients.
Advances in genetic technology and small molecule drug development have paved the way for clinical trials in Charcot‐Marie‐Tooth disease (CMT); however, the current FDA‐approved clinical trial outcome measures are insensitive to detect a meaningful clinical response. There is, therefore, a need to identify sensitive outcome measures or clinically relevant biomarkers. The aim of this study was to further evaluate plasma neurofilament light chain (NFL) as a disease biomarker in CMT. Plasma NFL was measured using SIMOA technology in both a cross‐sectional study of a US cohort of CMT patients and longitudinally over 6 years in a UK CMT cohort. In addition, plasma NFL was measured longitudinally in two mouse models of CMT2D. Plasma concentrations of NFL were increased in a US cohort of patients with CMT1B, CMT1X and CMT2A but not CMT2E compared with controls. In a separate UK cohort, over a 6‐year interval, there was no significant change in plasma NFL concentration in CMT1A or HSN1, but a small but significant reduction in patients with CMT1X. Plasma NFL was increased in wild type compared to GARSC201R mice. There was no significant difference in plasma NFL in GARSP278KY compared to wild type mice. In patients with CMT1A, the small difference in cross‐sectional NFL concentration vs healthy controls and the lack of change over time suggests that plasma NFL may lack sufficient sensitivity to detect a clinically meaningful treatment response in adulthood.
Migraine is the second largest cause of years lost to disability globally among all diseases, with a worldwide prevalence over 1 billion. Despite the global burden of migraine, few classes of therapeutics have been specifically developed to combat migraine. After 30 years of translational research, calcitonin gene-related peptide (CGRP) inhibitors have emerged as a promising new tool in the prevention of migraine. Like all new therapeutics; however, we have limited real-world experience and CGRP has several known systemic actions that warrant consideration. This article provides a narrative review of the evidence for CGRP antagonists and summarises the known and potential side effects that should be considered.
BackgroundPre-treatment screening for IgA deficiency and close monitoring of full blood count (FBC) and urea and electrolytes (U&E) is recommended with intravenous immunoglobulin (IVIg) therapy in neurological diseases. AimsTo examine the frequency of biochemically defined and clinically significant episodes of treatment associated haemolysis, neutropenia, thrombocytopenia and acute renal impairment in a cohort of patients on maintenance Immunoglobulin (Ig) therapy for inflammatory neuropathy. MethodsA retrospective review of routine blood monitoring in a cohort of patients from two UK specialist peripheral nerve centres. Accepted definitions for clinically and biochemically significant haemolysis, neutropenia, thrombocytopenia and acute kidney injury (AKI) were used.Results 1919 infusion episodes in 90 patients were analysed. Age (mean(S.D))= 58.09(14.4)years, 63% male, 72% CIDP (28% MMN), 97% IVIg (3% SCIg). Dose= 1.57 (0.79) g/kg/month or 97.1(37.3)g/infusion, frequency: 3.9 (1.4) weeks.Relative IgA deficiency was noted in 2 individuals (prevalence: 2.2%, 95% C.I.: 0-5.2) who received a combined total of 38 infusions (3800g IVIg) without adverse event. No clinically significant episodes of haemolysis, neutropenia, thrombocytopenia or AKI occurred in relation to treatment. An asymptomatic drop>10g/L haemoglobin (Hb) occurred in 3.5% (95% CI: 2.7-4.3) of treatment episodes in 38 individuals, mean reduction: 17.7(7.4)g/L; lowest Hb: 86g/L. Lower pre-treatment haemoglobin correlated with risk of recurrent episodes Ig-related drop (p:0.007). Two patients with chronic renal failure (stage 1 and 3) had received 28 (IV) and 104 (SC) infusions respectively, (6416g Ig) without impact on estimated glomerular filtration rate (eGFR). ConclusionsNo clinically significant Ig-related events were identified in this representative cohort. We suggest annual screening or clinically indicated testing as safe and more appropriate in long-term Ig use. Screening for IgA deficiency and baseline FBC and U&E may be helpful in identifying those at greater risk of complication.
Systemic amyloidosis can be hereditary or acquired. The autosomal dominant hereditary transthyretin amyloidosis and the acquired light-chain amyloidosis, the result of a plasma cell dyscrasia, are multisystem disorders with cardiovascular, autonomic and peripheral nerve involvement. There are numerous investigational modalities available to diagnose systemic amyloidosis and to assess the extent of organ involvement, but it is frequently misdiagnosed due to its heterogeneous clinical presentations and misleading investigation findings. An accurate and timely diagnosis of amyloid neuropathy can greatly impact on the outcomes for patients, especially as there will soon be new gene-silencing treatments for hereditary transthyretin amyloidosis.
Background and purpose: This study was undertaken to explore associations between plasma neurofilament light chain (pNfL) concentration (pg/ml) and disease activity in patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and examine the usefulness of pNfL concentrations in determining disease remission. Methods:We examined pNfL concentrations in treatment-naïve CIDP patients (n = 10) before and after intravenous immunoglobulin (IVIg) induction treatment, in pNfL concentrations in patients on maintenance IVIg treatment who had stable (n = 15) versus unstable disease (n = 9), and in clinically stable IVIg-treated patients (n = 10) in whom we suspended IVIg to determine disease activity and ongoing need for maintenance IVIg. pNfL concentrations in an age-matched healthy control group were measured for comparison.Results: Among treatment-naïve patients, pNfL concentration was higher in patients before IVIg treatment than healthy controls and subsequently reduced to be comparable to control group values after IVIg induction. Among CIDP patients on IVIg treatment, pNfL concentration was significantly higher in unstable patients than stable patients. A pNFL concentration > 16.6 pg/ml distinguished unstable treated CIDP from stable treated How to cite this article: Kapoor M, Carr A, Foiani M, et al. Association of plasma neurofilament light chain with disease activity in chronic inflammatory demyelinating polyradiculoneuropathy.
Microtubule-associated protein, Tau has been implicated in Alzheimer's disease for its detachment from microtubules and formation of insoluble intracellular aggregates within the neurons. Recent findings have suggested the expulsion of Tau seeds in the extracellular domain and their prion-like propagation between neurons. Transforming Growth Factor-β1 (TGF-β1) is a ubiquitously occurring cytokine reported to carry out immunomodulation and neuroprotection in the brain. TGF-β-mediated regulation occurs at the level of neuronal survival and differentiation, glial activation (astrocyte and microglia), amyloid production–distribution–clearance and neurofibrillary tangle formation, all of which contributes to Alzheimer's pathophysiology. Its role in the reorganization of cytoskeletal architecture and remodelling of extracellular matrix to facilitate cellular migration has been well-documented. Microglia are the resident immune sentinels of the brain responsible for surveying the local microenvironment, migrating towards the beacon of pertinent damage and phagocytosing the cellular debris or patho-protein deposits at the site of insult. Channelizing microglia to target extracellular Tau could be a good strategy to combat the prion-like transmission and seeding problem in Alzheimer's disease. The current review focuses on reaffirming the role of TGF-β1 signalling in Alzheimer’s pathology and cytoskeletal reorganization and considers utilizing the approach of TGF-β-triggered microglia-mediated targeting of extracellular patho-protein, Tau, as a possible potential strategy to combat Alzheimer's disease.
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