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Roadmap for C9ORF72 in Frontotemporal Dementia and Amyotrophic Lateral Sclerosis: Report on the C9ORF72 FTD/ALS Summit.
A summit held March 2023 in Scottsdale, Arizona (USA) focused on the intronic hexanucleotide expansion in the C9ORF72 gene and its relevance in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS; C9ORF72-FTD/ALS). The goal of this summit was to connect basic scientists, clinical researchers, drug developers, and individuals affected by C9ORF72-FTD/ALS to evaluate how collaborative efforts across the FTD-ALS disease spectrum might break down existing disease silos. Presentations and discussions covered recent discoveries in C9ORF72-FTD/ALS disease mechanisms, availability of disease biomarkers and recent advances in therapeutic development, and clinical trial design for prevention and treatment for individuals affected by C9ORF72-FTD/ALS and asymptomatic pathological expansion carriers. The C9ORF72-associated hexanucleotide repeat expansion is an important locus for both ALS and FTD. C9ORF72-FTD/ALS may be characterized by loss of function of the C9ORF72 protein and toxic gain of functions caused by both dipeptide repeat (DPR) proteins and hexanucleotide repeat RNA. C9ORF72-FTD/ALS therapeutic strategies discussed at the summit included the use of antisense oligonucleotides, adeno-associated virus (AAV)-mediated gene silencing and gene delivery, and engineered small molecules targeting RNA structures associated with the C9ORF72 expansion. Neurofilament light chain, DPR proteins, and transactive response (TAR) DNA-binding protein 43 (TDP-43)-associated molecular changes were presented as biomarker candidates. Similarly, brain imaging modalities (i.e., magnetic resonance imaging [MRI] and positron emission tomography [PET]) measuring structural, functional, and metabolic changes were discussed as important tools to monitor individuals affected with C9ORF72-FTD/ALS, at both pre-symptomatic and symptomatic disease stages. Finally, summit attendees evaluated current clinical trial designs available for FTD or ALS patients and concluded that therapeutics relevant to FTD/ALS patients, such as those specifically targeting C9ORF72, may need to be tested with composite endpoints covering clinical symptoms of both FTD and ALS. The latter will require novel clinical trial designs to be inclusive of all patient subgroups spanning the FTD/ALS spectrum.
Double-negative neuromyelitis optica spectrum disorder.
Most patients with neuromyelitis optica spectrum disorders (NMOSD) test positive for aquaporin-4 antibody (AQP4-IgG) or myelin oligodendrocyte glycoprotein antibodies (MOG-IgG). Those who are negative are termed double-negative (DN) NMOSD and may constitute a diagnostic and therapeutic challenge. DN NMOSD is a syndrome rather than a single disease, ranging from a (postinfectious) monophasic illness to a more chronic syndrome that can be indistinguishable from AQP4-IgG+ NMOSD or develop into other mimics such as multiple sclerosis. Thus, underlying disease mechanisms are likely to be heterogeneous. This topical review aims to (1) reappraise antibody-negative NMOSD definition as it has changed over time with the development of the AQP4 and MOG-IgG assays; (2) outline clinical characteristics and the pathophysiological nature of this rare entity by contrasting its differences and similarities with antibody-positive NMOSD; (3) summarize laboratory characteristics and magnetic resonance imaging findings of DN NMOSD; and (4) discuss the current treatment for DN NMOSD.
Outcomes of Percutaneous Access to the First Versus Third Segment of Axillary Artery During Aortic Procedures.
PURPOSE: This article aims at investigating the outcomes of percutaneous access via the first versus third axillary artery (AXA) segments with closure devices during aortic procedures. MATERIALS AND METHODS: All patients receiving percutaneous AXA access closed with Perclose ProGlide device (Abbott, Santa Clara, California) from 2008 to 2021 were included in a retrospective multicenter registry (NCT: 04589962). Efficacy endpoint was the technically successful percutaneous procedure (no open conversion). Safety endpoints were stroke and access complications according to the Valve Academic Research Consortium-3 reporting standards. The first (AXA1) or third (AXA3) axillary puncture sites were compared. RESULTS: A total of 412 percutaneous AXA accesses were included: 172 (42%) in AXA1 and 240 (58%) in AXA3. Left AXA was catheterized in 363 cases (76% of AXA1 vs 97% of AXA3, p<0.001) and 91% of fenestrated/branched endovascular repair (F/BEVAR) procedures were conducted from the left. A ≥12F internal diameter (ID) sheath was used in 49% of procedures. Open conversion rate was 1%, no major vascular complications occurred, and only one major non-vascular complication was recorded. Primary closure failure occurred in 18 AXA1 (11%) and 32 AXA3 accesses (13%), treated by covered (8.3%) or bare-metal (2.7%) stenting. Bailout stent patency was 100% at median follow-up of 12 months, with 6 of 6 stents still patent after >36 months of follow-up. Stroke rate was 4.4%. An introducer sheath >12F was independently associated with both access complications (p<0.001) and stroke (p=0.005), while a right-side access was associated with stroke only (p=0.034). Even after adjustment for covariates, AXA1 versus AXA3 showed an equal success rate (odds ratio [OR]=0.537, 95% confidence interval [CI]=0.011-1.22 for AXA3, p=0.104). The combination of AXA3 and a >10F introducer sheath provided worse outcomes compared with >10F sheaths through AXA1 (OR for success=0.367, 95% CI=0.176-0.767, p=0.008). This was not confirmed for >12F sheaths, associated with similar outcomes (p=0.31 AXA 1 vs AXA 3). CONCLUSION: Major local complications with the percutaneous axillary approach and ≤12F sheaths are infrequent and solvable by complementary endovascular interventions. Stroke risk remains an issue. First and third AXA segments are both amenable for access with good results, but larger sheaths (12F) perform better in AXA1. CLINICAL IMPACT: Percutaneous access with vascular closure devices at the first or third axillary artery (AXA) segments during aortic procedures is burdened by a negligible risk of open conversion. Local complications with the percutaneous axillary approach are infrequent and solvable by complementary endovascular interventions. First and third AXA segments are both amenable to access with excellent results, but larger sheaths (12F) perform better in the wider first AXA segment. In this setting, bailout stenting does not appear to be associated with mid-term stent occlusion.
Association Between Clinical Factors and Result of Immune Checkpoint Inhibitor Related Myasthenia Gravis: A Single Center Experience and Systematic Review.
BACKGROUND: Neurological immune-related adverse events (nirAEs) are rare toxicities of immune-checkpoint inhibitors (ICI). With the increase use of ICIs, incidence of nirAEs is growing, among which ICI related MG (irMG) is causing high fatality rate. Given the limited evidence, data from a large cohort of patients with irMG is needed to aid in recognition and management of this fatal complication. OBJECTIVE: This study aimed to summarize clinical characteristics of irMG and explore predictors of irMG clinical outcome. METHODS: We summarized our institution's patients who were diagnosed as irMG between Sep 2019 and Oct 2021. We systematically reviewed the literature through Oct 2021 to identify all similar reported patients who met inclusion criteria. As the control group, patients with idiopathic MG were used. We collected data on clinical features, management, and outcomes of both irMG and idioMG cases. Further statistical analysis was conducted. RESULTS: Sixty three irMG patients and 380 idioMG patients were included in the final analysis. For irMG patients, six were from our institution while the rest 57 were from reported cases. The average age of irMG patients is 70.16 years old. Forty three were male. Average time from first ICI injection to symptom onset was 5.500 weeks. Eleven patients had a past history of MG. Higher MGFA classification and higher QMGS rates were observed in irMG patients compared to idioMG patients. For complication, more irMG patients had myositis or myocarditis overlapping compared to idioMG patients. The most commonly used treatment was corticosteroids for both idioMG and irMG. Twenty one patients (35%) with irMG had unfavorable disease outcome. Single variate and multivariate binary logistic regression proved that association with myocarditis, high MGFA classification or QMGS rates at first visit were negatively related to disease outcome in irMG patients. CONCLUSION: irMG is a life-threatening adverse event. irMG has unique clinical manifestations and clinical outcome compared to idioMG. When suspicious, early evaluation of MGFA classification, QMGS rates and myositis/myocarditis evaluation are recommended.
Iron metabolism patterns in non-anemic patients with myasthenia gravis: A cross-sectional and follow-up study.
BACKGROUND AND PURPOSE: Iron metabolism in myasthenia gravis (MG) and factors associated with it are explored by few published studies. Therefore, this study aimed to compare iron metabolism patterns between patients with MG and healthy individuals as well as between the same group of patients before and after immunotherapy, and to identify predictors of iron metabolism disorders in MG. MATERIALS AND METHODS: For this study, 105 patients and healthy individuals were included at baseline, after which paired parametric and non-parametric tests were adopted to compare their iron metabolism patterns, and multivariate binary logistic regression was used to identify predictors of iron metabolism disorders. Patients with MG were then followed up for 12 ± 3 months to explore alterations in their iron metabolism patterns after starting immunotherapy with the help of paired tests. RESULTS: Non-anemic immunotherapy-naive patients with MG had significantly lower serum iron (SI) and transferrin saturation (TS) levels than healthy individuals. Premenopausal female was significantly associated with SI < 65 μg/dL and iron deficiency in these patients. However, iron metabolism parameters did not significantly alter after around 12 months of immunotherapy in patients with MG. CONCLUSION: Iron inadequacy was present in patients with MG, particularly premenopausal female patients, and it would hardly improve after immunotherapy. Given the significant role of iron in human body, it should be given more attention in patients with MG.
Long-Term Efficacy of Non-steroid Immunosuppressive Agents in Anti-Muscle-Specific Kinase Positive Myasthenia Gravis Patients: A Prospective Study.
BACKGROUND AND PURPOSE: Anti-muscle-specific kinase (MuSK) positive myasthenia gravis (MG) is characterized by a high relapsing rate, thus, choosing the appropriate oral drug regimen is a challenge. This study aimed to evaluate the efficacy of oral immunosuppressants (IS) in preventing relapse in MuSK-MG. METHODS: This prospective cohort observational study included patients with MuSK-MG at Peking Union Medical College Hospital between January 1, 2018, and November 15, 2021. The patients were divided into 2 groups: those with (IS+) or without (IS-) non-steroid immunosuppressive agents. The primary outcome was relapsed at follow-up, and the log-rank test was used to compare the proportion of maintenance-free relapse between the groups; hazard ratio (HR) was calculated using the Cox proportional hazards models. RESULTS: Fifty-three of 59 patients with MuSK-MG were included in the cohort, 14 were in the IS+ group, and 39 were in the IS- group. Twenty-four cases in the cohort experienced relapse at least once; the relapse rate was 2/14 (14.3%) in the IS+ group and 22/39 (56.4%) in the IS- group. At the end of follow-up, the proportion of maintenance-free relapse was significantly different between the two groups (log-rank χ2 = 4.94, P = 0.02). Of all the potential confounders, only the use of IS was associated with a reduced risk of relapse. The HR for relapse among patients in the IS+ group was 0.21 (95%CI 0.05-0.58) and was 0.23 (95%CI 0.05-0.93) in a model adjusted for age, sex, relapse history, highest Myasthenia Gravis Foundation of America (MGFA), and accumulated time of steroid therapy. CONCLUSIONS: This study provides evidence that oral non-steroid immunosuppressive agents may be beneficial in reducing relapse in patients with MuSK-MG.
Patients With Myasthenia Gravis With Acute Onset of Dyspnea: Predictors of Progression to Myasthenic Crisis and Prognosis.
Background: Life-threatening myasthenic crisis (MC) occurs in 10-20% of the patients with myasthenia gravis (MG). It is important to identify the predictors of progression to MC and prognosis in the patients with MG with acute exacerbations. Objective: This study aimed to explore the predictors of progression to MC in the patients with MG with acute onset of dyspnea and their short-term and long-term prognosis. Methods: This study is a retrospective cohort study. We collected and analyzed data on all the patients with MG with acute dyspnea over a 10-year period in a single center using the univariate and multivariate analysis. Results: Eighty-six patients with MG were included. In their first acute dyspnea episodes, 36 (41.9%) episodes eventually progressed to MC. A multivariate analysis showed that the early-onset MG (adjusted OR: 3.079, 95% CI 1.052-9.012) and respiratory infection as a trigger (adjusted OR: 3.926, 95% CI 1.141-13.510) were independent risk factors for the progression to MC, while intravenous immunoglobulin (IVIg) treatment prior to the mechanical ventilation (adjusted OR: 0.253, 95% CI 0.087-0.732) was a protective factor. The prognosis did not significantly differ between the patients with and without MC during the MG course, with a total of 45 (52.3%) patients reaching post-intervention status better than minimal manifestations at the last follow-up. Conclusion: When treating the patients with MG with acute dyspnea, the clinicians should be aware of the risk factors of progression to MC, such as early-onset MG and respiratory infection. IVIg is an effective treatment. With proper immunosuppressive therapy, this group of patients had an overall good long-term prognosis.
Perioperative Bilateral Medial Medullary Infarction With "Snake Eyes Appearance": A Case Report.
Perioperative bilateral medial medullary infarction (BMMI) cases mimicking acute motor axonal neuropathy (AMAN) under general anesthesia have not been reported. We describe a patient who suffered flaccid quadriplegia and could not wean from mechanical ventilation after emergence from general anesthesia in cardiac surgery. A diagnosis of AMAN was considered, but intravenous immunoglobulin showed little efficacy. Magnetic resonance imaging of the patient later revealed BMMI with "snake eyes appearance," and he was found to have severe vertebral artery stenosis. Considering the association between severe coronary heart disease and cerebrovascular stenosis, we highlight the significance of preoperative evaluation and comprehensive management of the cerebrovascular system for certain patients.
Iron metabolism in non-anemic myasthenia gravis patients: A cohort study.
BACKGROUND: The association of iron metabolism parameters with disease severity and outcome in myasthenia gravis (MG) patients has not been reported. This study was conducted to determined clinical factors including iron metabolism parameters correlated with disease severity and future outcome in non-anemic immunotherapy-naïve MG patients first receiving immunotherapy. MATERIAL AND METHODS: One hundred and ten patients were included at baseline to explore predictor variables associated with disease severity represented by variables derived from MG activities of daily living (MG-ADL) score using multivariate logistic regression, after which 103 and 98 patients were included respectively in multivariate survival analyses at 6-month and 12-month follow-up to identify predictors for minimal manifestation status (MMS) after starting immunotherapy. RESULTS: Higher ferritin level was independently associated with higher risk of severe generalized disease in non-anemic immunotherapy-naïve MG patients. Total iron binding capacity <250 μg/dL and the interval between onset and immunotherapy <1 year were independent predictors for MMS at 6-month and 12-month follow-up after initiating immunotherapy. Transferrin <2.00 g/L was an independent predictor for MMS at 12-month follow-up. CONCLUSION: Iron metabolism parameters might be promising biomarkers for evaluating disease severity and guiding therapeutic decision in MG patients.
Interplay Between Chronic Kidney Disease, Hypertension, and Stroke: Insights From a Multivariable Mendelian Randomization Analysis.
BACKGROUND AND OBJECTIVES: Chronic kidney disease (CKD) increases the risk of stroke, but the extent through which this association is mediated by hypertension is unknown. We leveraged large-scale genetic data to explore causal relationships between CKD, hypertension and cerebrovascular disease phenotypes. METHODS: We used data from genome-wide association studies (GWAS) of European ancestry to identify genetic proxies for kidney function (CKD diagnosis, estimated glomerular filtration rate [eGFR], and urinary albumin-to-creatinine ratio [UACR]), systolic blood pressure (SBP), and cerebrovascular disease (ischaemic stroke and its subtypes, and intracerebral haemorrhage [ICH). We then conducted univariable, multivariable and mediation Mendelian randomization (MR) analyses to investigate the effect of kidney function on stroke risk and the proportion of this effect mediated through hypertension. RESULTS: Univariable Mendelian randomization revealed associations between genetically determined lower eGFR and risk of all stroke (OR per 1-log decrement in eGFR, 1.77; 95% CI, 1.31-2.40; p<0.001), ischaemic stroke (OR, 1.81; 95% CI, 1.31-2.51; p<0.001), and most strongly with large artery stroke (LAS) (OR, 3.00; 95% CI, 1.33-6.75; p=0.008). These associations remained significant in the multivariable MR analysis, controlling for SBP (OR, 1.98; 95% CI, 1.39-2.82; p<0.001 for AS; OR, 2.16; 95% CI, 1.48-3.17; p<0.001 for IS; OR, 4.35; 95% CI, 1.84-10.27; p=0.001 for LAS), with only a small proportion of the total effects mediated by SBP (6.5% [0.7-16.8%], 6.6% [0.8-18.3%] and 7.2% [0.5-24.8%], respectively). Total, direct and indirect effect estimates were similar across a number of sensitivity analyses (Weighted median, MR-Egger regression). DISCUSSION: Our results demonstrate an independent causal effect of impaired kidney function, as assessed by decreased eGFR, on stroke risk, particularly LAS, even when controlled for SBP. Targeted prevention of kidney disease could lower atherosclerotic stroke risk independent of hypertension.
Correlation Between Fundus Autofluorescence Pattern and Retinal Function on Microperimetry in Choroideremia.
PURPOSE: In patients with choroideremia, it is not known how smooth and mottled patterns on short-wavelength fundus autofluorescence (AF) imaging relate to retinal function. METHODS: A retrospective case-note review was undertaken on 190 patients with choroideremia at two specialist centers for retinal genetics. Twenty patients with both smooth and mottled zones on short-wavelength AF imaging and concurrent mesopic microperimetry assessments were included. Mean retinal sensitivities within the smooth and mottled zones were compared between choroideremia patients, and identical points on mesopic microperimetry collected from 12 age-matched controls. Longitudinal analyses were undertaken at 2 and 5 years in a subset of patients. RESULTS: In patients with choroideremia, mean retinal sensitivities at baseline were significantly greater in the smooth zone (26.1 ± 2.0 dB) versus the mottled zone (20.5 ± 4.2 dB) (P < 0.0001). Mean retinal sensitivities at baseline were similar in the smooth zone between choroideremia patients and controls (P = 0.054) but significantly impaired in the mottled zone in choroideremia compared to controls (P < 0.0001). The rate of decline in total sensitivity over 5 years was not significant in either the smooth or mottled zone in a small subset of choroideremia patients (n = 7; P = 0.344). CONCLUSIONS: In choroideremia, retinal sensitivity as determined by microperimetry correlates with patterns on AF imaging: retinal function in the smooth zone, where the retinal pigment epithelium is anatomically preserved, is similar to controls, but retinal sensitivity in the mottled zone is impaired. TRANSLATIONAL RELEVANCE: Patterns on AF imaging may represent a novel, objective outcome measure for clinical trials in choroideremia as a surrogate for retinal function.
Multimodal layer modelling reveals in vivo pathology in amyotrophic lateral sclerosis.
Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease characterised by the loss of motor control. Current understanding of ALS pathology is largely based on post-mortem investigations at advanced disease stages. A systematic in-vivo description of the microstructural changes that characterise early-stage ALS, and their subsequent development, is so far lacking. Recent advances in ultra-high field (7 T) MRI data modelling allow us to investigate cortical layers in-vivo. Given the layer-specific and topographic signature of pathology in ALS, we combined submillimeter structural 7T-MRI data (qT1, QSM), functional localisers of body parts (upper limb, lower limb, face) and automated layer modelling to systematically describe pathology in the primary motor cortex (M1), in 12 living ALS-patients with reference to 12 age-, gender-, handedness- and education-matched controls. Longitudinal sampling was performed for a subset of patients. We calculated multimodal pathology maps for each layer (superficial layer, layer 5a, layer 5b, layer 6) of M1 to identify hotspots of demyelination, iron and calcium accumulation in different cortical fields. We show preserved mean cortical thickness and layer architectures of M1, despite significantly increased iron in layer 6 and significantly increased calcium in layer 5a and superficial layer, in patients compared to controls. The behaviorally first-affected cortical field shows significantly increased iron in L6 compared to other fields, while calcium accumulation is atopographic and significantly increased in the low-myelin borders between cortical fields compared to the fields themselves. A subset of patients with longitudinal data shows that the low-myelin borders are particularly disrupted, and that calcium hotspots but to a lesser extent iron hotspots precede demyelination. Finally, we highlight that a very-slow progressing patient (P4) shows a distinct pathology profile compared to the other patients. Our data shows that layer-specific markers of in-vivo pathology can be identified in ALS-patients with a single 7T-MRI measurement after first diagnosis, and that such data provide critical insights into the individual disease state. Our data highlight the non-topographic architecture of ALS disease spread, and the role of calcium rather than iron accumulation in predicting future demyelination. We also highlight a potentially important role of low-myelin borders, that are known to connect to multiple areas within the M1 architecture, in disease spread. Importantly, the distinct pathology profile of a very-slow progressing patient (P4) highlights a distinction between disease duration and pathology progression. Our findings demonstrate the importance of in-vivo histology for the diagnosis and prognosis of neurodegenerative diseases such as ALS.
Clinical Research on the Leading Causes of Severe Sight Impairment in the UK General and Working Populations.
PURPOSE: Clinical research brings the potential of improved diagnostics, sight-saving treatments, and more accessible services to those suffering with severe sight impairment (SSI). This report investigates whether registered ophthalmology clinical studies address the leading causes of SSI in the general and working populations of the United Kingdom (UK). METHODS: The latest statistics on the leading causes of SSI in the UK general and working populations were identified by searching PubMed, Cochrane Library, and TRIP databases. Clinical study registries were searched to identify registered clinical studies (on or prior to 1st December 2022) on the leading causes of SSI. The relationship between the number of clinical studies on leading causes of SSI and the percentage of SSI certifications they account for was analyzed. RESULTS: In the UK general population, the number of registered clinical studies on the leading causes of SSI is statistically significantly correlated (Spearman's rho = 0.86, p < 0.01) with the percentage of SSI certifications they account for. However, there is no correlation between the two in the UK working population (aged 16-64) (Spearman's rho = 0.15, p = 0.70). Eye conditions accounting for the most SSI certifications in individuals of working age have significantly less clinical research activity than those that cause the most SSI certifications in the general population. Out of the leading causes of SSI certifications studied, disorders of the visual cortex and congenital anomalies of the eye have the least clinical research activity. CONCLUSION: Clinical research into the leading causes of SSI in the general population is essential. However, it is important to consider eye conditions that cause the most severe visual impairment in individuals of working age due to the significant health and socioeconomic implications of sight loss in this population.
A translational roadmap for transcranial magnetic and direct current stimulation in stroke rehabilitation: Consensus-based core recommendations from the third stroke recovery and rehabilitation roundtable.
BACKGROUND AND AIMS: The purpose of this Third Stroke Recovery and Rehabilitation Roundtable (SRRR3) was to develop consensus recommendations to address outstanding barriers for the translation of preclinical and clinical research using the non-invasive brain stimulation (NIBS) techniques Transcranial Magnetic Stimulation (TMS) and Transcranial Direct Current Stimulation (tDCS) and provide a roadmap for the integration of these techniques into clinical practice. METHODS: International NIBS and stroke recovery experts (N = 18) contributed to the consensus process. Using a nominal group technique, recommendations were reached via a five-stage process, involving a thematic survey, two priority ranking surveys, a literature review and an in-person meeting. RESULTS AND CONCLUSIONS: Results of our consensus process yielded five key evidence-based and feasibility barriers for the translation of preclinical and clinical NIBS research, which were formulated into five core consensus recommendations. Recommendations highlight an urgent need for (1) increased understanding of NIBS mechanisms, (2) improved methodological rigor in both preclinical and clinical NIBS studies, (3) standardization of outcome measures, (4) increased clinical relevance in preclinical animal models, and (5) greater optimization and individualization of NIBS protocols. To facilitate the implementation of these recommendations, the expert panel developed a new SRRR3 Unified NIBS Research Checklist. These recommendations represent a translational pathway for the use of NIBS in stroke rehabilitation research and practice.
Ultrasensitive assay technology and fluid biomarkers for the evaluation of peripheral nerve disease.
The field of biomarker discovery is rapidly expanding. The introduction of ultrasensitive immunoassays and the growing precision of genetic technologies are poised to revolutionise the assessment and monitoring of many diseases. Given the difficulties in imaging and tissue diagnosis, there is mounting interest in serum and cerebrospinal fluid biomarkers of peripheral neuropathy. Realised and potential fluid biomarkers of peripheral nerve disease include neuronal biomarkers of axonal degeneration, glial biomarkers for peripheral demyelinating disorders, immunopathogenic biomarkers (such as the presence and titre of antibodies or the levels of cytokines) and genetic biomarkers. Several are already starting to inform clinical practice, whereas others remain under evaluation as potential indicators of disease activity and treatment response. As more biomarkers become available for clinical use, it has become increasingly difficult for clinicians and researchers to keep up-to-date with the most recent discovery and interpretation. In this review, we aim to inform practising neurologists, neuroscientists and other clinicians about recent advances in fluid biomarker technology, with a focus on single molecule arrays (Simoa), chemiluminescent enzyme immunoassays (CLEIA), electrochemiluminescence (ECL), proximity extension assays (PEA), and microfluidic technology. We discuss established and emerging fluid biomarkers of peripheral neuropathy, their clinical applications, limitations and potential future developments.
Natural and vaccine-induced antibody and cellular responses against emerging SARS-CoV-2 variants of concern
Abstract Both natural infection with SARS-CoV-2 and immunization with a number of vaccines induce protective immunity. However, the ability of such immune responses to recognize and therefore protect against emerging variants is a matter of increasing importance. Such variants of concern (VOC) include isolates of lineage B1.1.7, first identified in the UK, and B1.351, first identified in South Africa. Our data confirm that VOC, particularly those with substitutions at residues 484 and 417 escape neutralization by antibodies directed to the ACE2-binding Class 1 and the adjacent Class 2 epitopes but are susceptible to neutralization by the generally less potent antibodies directed to Class 3 and 4 epitopes on the flanks RBD. To address this potential threat, we sampled a SARS-CoV-2 uninfected UK cohort recently vaccinated with BNT162b2 (Pfizer-BioNTech, two doses delivered 18-28 days apart), alongside a cohort naturally infected in the first wave of the epidemic in Spring 2020. We tested antibody and T cell responses against a reference isolate (VIC001) representing the original circulating lineage B and the impact of sequence variation in these two VOCs. We identified a reduction in antibody neutralization against the VOCs which was most evident in the B1.351 variant. However, the majority of the T cell response was directed against epitopes conserved across all three strains. The reduction in antibody neutralization was less marked in post-boost vaccine-induced than in naturally-induced immune responses and could be largely explained by the potency of the homotypic antibody response. However, after a single vaccination, which induced only modestly neutralizing homotypic antibody titres, neutralization against the VOCs was completely abrogated in the majority of vaccinees. These data indicate that VOCs may evade protective neutralising responses induced by prior infection, and to a lesser extent by immunization, particularly after a single vaccine, but the impact of the VOCs on T cell responses appears less marked. The results emphasize the need to generate high potency immune responses through vaccination in order to provide protection against these and other emergent variants. We observed that two doses of vaccine also induced a significant increase in binding antibodies to spike of both SARS-CoV-1 & MERS, in addition to the four common coronaviruses currently circulating in the UK. The impact of antigenic imprinting on the potency of humoral and cellular heterotypic protection generated by the next generation of variant-directed vaccines remains to be determined.