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Blood-based biomarkers have been extensively evaluated for their diagnostic potential in Alzheimer's disease. However, their relative prognostic and monitoring capabilities for cognitive decline, amyloid-β (Aβ) accumulation and grey matter loss in cognitively unimpaired elderly require further investigation over extended time periods. This prospective cohort study in cognitively unimpaired elderly [n = 185, mean age (range) = 69 (53-84) years, 48% female] examined the prognostic and monitoring capabilities of glial fibrillary acidic protein (GFAP), neurofilament light (NfL), Aβ1-42/Aβ1-40 and phosphorylated tau (pTau)181 through their quantification in serum. All participants underwent baseline Aβ-PET, MRI and blood sampling as well as 2-yearly cognitive testing. A subset additionally underwent Aβ-PET (n = 109), MRI (n = 106) and blood sampling (n = 110) during follow-up [median time interval (range) = 6.1 (1.3-11.0) years]. Matching plasma measurements were available for Aβ1-42/Aβ1-40 and pTau181 (both n = 140). Linear mixed-effects models showed that high serum GFAP and NfL predicted future cognitive decline in memory (βGFAP×Time = -0.021, PFDR = 0.007 and βNfL×Time = -0.031, PFDR = 0.002) and language (βGFAP×Time = -0.021, PFDR = 0.002 and βNfL×Time = -0.018, PFDR = 0.03) domains. Low serum Aβ1-42/Aβ1-40 equally but independently predicted memory decline (βAβ1-42/Aβ1-40×Time = -0.024, PFDR = 0.02). Whole-brain voxelwise analyses revealed that low Aβ1-42/Aβ1-40 predicted Aβ accumulation within the precuneus and frontal regions, high GFAP and NfL predicted grey matter loss within hippocampal regions and low Aβ1-42/Aβ1-40 predicted grey matter loss in lateral temporal regions. Serum GFAP, NfL and pTau181 increased over time, while Aβ1-42/Aβ1-40 decreased only in Aβ-PET-negative elderly. NfL increases associated with declining memory (βNfLchange×Time = -0.030, PFDR = 0.006) and language (βNfLchange×Time = -0.021, PFDR = 0.02) function and serum Aβ1-42/Aβ1-40 decreases associated with declining language function (βAβ1-42/Aβ1-40×Time = -0.020, PFDR = 0.04). GFAP increases associated with Aβ accumulation within the precuneus and NfL increases associated with grey matter loss. Baseline and longitudinal serum pTau181 only associated with Aβ accumulation in restricted occipital regions. In head-to-head comparisons, serum outperformed plasma Aβ1-42/Aβ1-40 (ΔAUC = 0.10, PDeLong, FDR = 0.04), while both plasma and serum pTau181 demonstrated poor performance to detect asymptomatic Aβ-PET positivity (AUC = 0.55 and 0.63, respectively). However, when measured with a more phospho-specific assay, plasma pTau181 detected Aβ-positivity with high performance (AUC = 0.82, PDeLong, FDR < 0.007). In conclusion, serum GFAP, NfL and Aβ1-42/Aβ1-40 are valuable prognostic and/or monitoring tools in asymptomatic stages providing complementary information in a time- and pathology-dependent manner., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background and Objectives: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a clinically heterogeneous immune-mediated disease. Diagnostic biomarkers for CIDP are currently lacking. Peptides derived from the variable domain of circulating immunoglobulin G (IgG) have earlier been shown to be shared among patients with the same immunologic disease. Because humoral immune factors are hypothesized to be involved in the pathogenesis of CIDP, we evaluated IgG variable domain-derived peptides as diagnostic biomarkers in CIDP (primary objective) and whether IgG-derived peptides could cluster objective clinical entities in CIDP (secondary objective)., Methods: IgG-derived peptides were determined in prospectively collected sera of patients with CIDP and neurologic controls by means of mass spectrometry. Peptides of interest were selected through statistical analysis in a discovery cohort followed by sequence determination and confirmation. Diagnostic performance was evaluated for individual selected peptides and for a multipeptide model incorporating selected peptides, followed by performance reassessment in a validation cohort. Clustering of patients with CIDP based on IgG-derived peptides was evaluated through unsupervised sparse principal component analysis followed by k-means clustering., Results: Sixteen peptides originating from the IgG variable domain were selected as candidate biomarkers in a discovery cohort of 44 patients with CIDP and 29 neurologic controls. For all 16 peptides, univariate logistic regressions and ROC curve analysis demonstrated increasing peptide abundances to associate with increased odds for CIDP (area under the curves [AUCs] ranging from 64.6% to 79.6%). When including age and sex in the logistic regression models, this remained the case for 13/16 peptides. A model composed of 5/16 selected peptides showed strong discriminating performance between patients with CIDP and controls (AUC 91.5%; 95% CI 84.6%-98.4%; p < 0.001). In the validation cohort containing 45 patients and 43 controls, 2/16 peptides demonstrated increasing abundances to associate with increased odds for CIDP, while the five-peptide model demonstrated an AUC of 61.2% (95% CI 49.3%-73.2%; p = 0.064). Peptide-based patient clusters did not associate with clinical features., Discussion: IgG variable domain-derived peptides showed a valid source for diagnostic biomarkers in CIDP, albeit with challenges toward replication. Our proof-of-concept findings warrant further study of IgG-derived peptides as biomarkers in more homogeneous cohorts of patients with CIDP and controls., Classification of Evidence: This study provides Class III evidence that the pattern of serum IgG-derived peptide clusters may help differentiate between patients with CIDP and those with other peripheral neuropathies., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Aims: To explore the relationship between inflammatory markers and sarcopenia-related traits in sarcopenic older adults., Methods: Baseline data of the ongoing Exercise and Nutrition for Healthy AgeiNg (ENHANce) study were used for a secondary, exploratory, cross-sectional analysis. ENHANce is a 5-armed triple blinded randomized controlled trial, in older adults (>65y) with sarcopenia defined according to the revised criteria of the European Working Group of Sarcopenia in Older People (EWGSOP2) aiming to assess the effect of combined anabolic interventions (protein supplement, omega-3 supplement and physical exercise) on physical performance, compared to single/placebo interventions. Inflammatory markers C-reactive protein (hs-CRP), albumin, interleukin-1β (IL-1β), IL-6, IL-8, and tumour necrosis factor-α (TNF-α) were assessed at baseline. Spearman's rho (ρ) correlation coefficients were calculated to associate these inflammatory markers with baseline sarcopenia-defining parameters (handgrip strength, chair stand test, appendicular lean mass [aLM], gait speed, Short Physical Performance Battery), physical activity (step count) and quality of life (SF-36, SarQoL)., Results: We included 40 sarcopenic subjects (15 men/25 women, age 77.1 ± 6.8 years). Contrary to expectations, the pro-inflammatory IL-1β correlated positively with handgrip strength (ρ: 0.376; p = 0.024) and IL-6 with aLM (ρ: 0.334; p = 0.0433). IL-6 inversely correlated with step count (ρ:-0.358; p = 0.048). Subgroup analysis revealed important gender differences. IL-8 inversely correlated with handgrip strength in women (ρ: -0.425; p = 0.034) but not in men. In contrast, pro-inflammatory cytokines CRP (ρ: -0.615; p = 0.019), IL-6 (ρ: -0.604; p = 0.029) and TNF-α (ρ: -0.615; p = 0.025) inversely correlated with the SF-36 physical component score in men but not in women., Conclusion: Although Inflammageing might play a role in sarcopenia-related traits, this exploratory study highlights an important role of gender. Future research should take this into account when elucidating the Inflammageing-sarcopenia interplay., Competing Interests: Declaration of competing interest EG is a board member of the Belgian Bone Club. EG has received consultancy fees and lectures fees from Alexion, Amgen, Sandoz, Takeda, UCB, unrelated to this work. None of the other authors have any conflicts of interest to declare related to this manuscript., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: The current practice of quantifying cerebrospinal fluid (CSF) biomarkers as an aid in the diagnosis of Alzheimer's disease (AD) varies from center to center. For a same biochemical profile, interpretation and reporting of results may differ, which can lead to misunderstandings and raises questions about the commutability of tests., Methods: We obtained a description of (pre-)analytical protocols and sample reports from 40 centers worldwide. A consensus approach allowed us to propose harmonized comments corresponding to the different CSF biomarker profiles observed in patients., Results: The (pre-)analytical procedures were similar between centers. There was considerable heterogeneity in cutoff definitions and report comments. We therefore identified and selected by consensus the most accurate and informative comments regarding the interpretation of CSF biomarkers in the context of AD diagnosis., Discussion: This is the first time that harmonized reports are proposed across worldwide specialized laboratories involved in the biochemical diagnosis of AD., (© 2021 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Objective: To investigate biomarkers of disease progression in cerebrospinal fluid (CSF) and serum in adult patients with spinal muscular atrophy (SMA). Furthermore, we assess the clinical response to nusinersen treatment in adults with SMA over a longer follow-up period than the previously reported 6-14 months., Methods: We included 16 adults with SMA type 3-4 for nusinersen treatment over 22 months in this prospective study. We evaluated chitotriosidase-1 (CHIT1) and chitinase-3-like protein 1 (YKL-40) as neuroinflammatory biomarkers in CSF, and neurofilament light chain (NfL) and heavy chain (pNfH) as neurodegenerative markers in CSF and serum at baseline, month 6, 14 and 22, together with a wide range of clinical outcome measures., Results: Levels of CHIT1 increased significantly (p = 0.048) throughout the 22-month treatment period and pNfH decreased significantly (p = 0.022) in CSF, but both did not correlate with clinical outcome measures. YKL-40 correlated strongly with neurofilaments in CSF (rho = 0.76) and decreased significantly (p = 0.037) in patients with improvements in the revised upper limb module (RULM). Finally, patients showed significant improvements in hand grip strength, hand motor function, medical research council (MRC) sum score, and peak expiratory flow (PEF) after 22 months of treatment., Interpretation: YKL-40 in CSF correlated with clinical improvements during nusinersen treatment. In contrast, CHIT1 and pNfH in CSF changed significantly during treatment but did not correlate with clinical outcomes. Finally, we demonstrated a sustained clinical effect of nusinersen treatment in adults after 22 months., (© 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disorder characterized by progressive degeneration of motor neurons (MNs). Most cases are sporadic, whereas 10% are familial. The pathological mechanisms underlying the disease are partially understood, but it is increasingly being recognized that alterations in RNA metabolism and deregulation of microRNA (miRNA) expression occur in ALS. In this study, we performed miRNA expression profile analysis of iPSC-derived MNs and related exosomes from familial patients and healthy subjects. We identified dysregulation of miR-34a, miR-335 and miR-625-3p expression in both MNs and exosomes. These miRNAs regulate genes and pathways which correlate with disease pathogenesis, suggesting that studying miRNAs deregulation can contribute to deeply investigate the molecular mechanisms underlying the disease. We also assayed the expression profile of these miRNAs in the cerebrospinal fluid (CSF) of familial (fALS) and sporadic patients (sALS) and we identified a significant dysregulation of miR-34a-3p and miR-625-3p levels in ALS compared to controls. Taken together, all these findings suggest that miRNA analysis simultaneously performed in different human biological samples could represent a promising molecular tool to understand the etiopathogenesis of ALS and to develop new potential miRNA-based strategies in this new propitious therapeutic era., (© 2022. The Author(s).)

Objective: The primary study objective of this retrospective academic memory clinic-based observational longitudinal study was to investigate the prognostic value of a cerebrospinal fluid (CSF)-based ATN classification for subsequent cognitive decline during the 3 years following lumbar puncture in a clinical, real-life setting. The secondary objective was to investigate the prognostic value of CSF biomarkers as continuous variables., Methods: Data from 228 patients (median age 67 (47-85) years), who presented at the Neurology Memory Clinic UZ/KU Leuven between September 2011 and December 2016, were included with a follow-up period of up to 36 months. Patients underwent a CSF AD biomarker test for amyloid-beta 1-42 (Aβ 42 ) , hyperphosphorylated tau (p 181 -tau) and total tau (t-tau) in the clinical work-up for diagnostic reasons. Patients were divided into ATN classes based on CSF biomarkers: Aβ 42 for amyloid (A), p 181 -tau for tau (T), and t-tau as a measure for neurodegeneration (N). Based on retrospective data analysis, cognitive performance was evaluated by Mini Mental State Examination (MMSE) scores every 6 months over a period up to 36 months following the lumbar puncture. The statistical analysis was based on linear mixed-effects modeling (LME)., Results: The distribution in the current clinical sample was as follows: A-/T-/N- 32.02%, A+/T-/N- 33.33%, A+/T+/N+ 17.11%, A+/T-/N+ 11.84%, A-/T-/N+ 4.39%, A-/T+/N+ 1.32% (3 cases), with no cases in the A-/T+/N- and A+/T+/N- class. Hence, the latter 3 classes were excluded from further analyses. The change of MMSE relative to A-/T-/N- over a 36-month period was significant in all four ATN classes: A+/T+/N+ = - 4.78 points on the MMSE; A-/T-/N+ = - 4.76; A+/T-/N+ = - 2.83; A+/T-/N- = - 1.96. The earliest significant difference was seen in the A+/T+/N+ class at 12 months after baseline. The effect of ATN class on future cognitive decline was confirmed for a different set of CSF thresholds. All individual baseline CSF biomarkers including the Aβ 42 /t-tau ratio showed a significant correlation with subsequent cognitive decline, with the highest correlation seen for Aβ 42 /t-tau., Conclusion: ATN classification based on CSF biomarkers has a statistically significant and clinically relevant prognostic value for the course of cognitive decline in a 3-year period in a clinical practice setting.

Apart from well-defined factors in neuronal cells 1 , only a few reports consider that the variability of sporadic amyotrophic lateral sclerosis (ALS) progression can depend on less-defined contributions from glia 2,3 and blood vessels 4 . In this study we use an expression-weighted cell-type enrichment method to infer cell activity in spinal cord samples from patients with sporadic ALS and mouse models of this disease. Here we report that patients with sporadic ALS present cell activity patterns consistent with two mouse models in which enrichments of vascular cell genes preceded microglial response. Notably, during the presymptomatic stage, perivascular fibroblast cells showed the strongest gene enrichments, and their marker proteins SPP1 and COL6A1 accumulated in enlarged perivascular spaces in patients with sporadic ALS. Moreover, in plasma of 574 patients with ALS from four independent cohorts, increased levels of SPP1 at disease diagnosis repeatedly predicted shorter survival with stronger effect than the established risk factors of bulbar onset or neurofilament levels in cerebrospinal fluid. We propose that the activity of the recently discovered perivascular fibroblast can predict survival of patients with ALS and provide a new conceptual framework to re-evaluate definitions of ALS etiology.

Background: Blood-based amyloid biomarkers may provide a non-invasive, cost-effective and scalable manner for detecting cerebral amyloidosis in early disease stages., Methods: In this prospective cross-sectional study, we quantified plasma Aβ 1-42 /Aβ 1-40 ratios with both routinely available ELISAs and novel SIMOA Amyblood assays, and provided a head-to-head comparison of their performances to detect cerebral amyloidosis in a nondemented elderly cohort (n = 199). Participants were stratified according to amyloid-PET status, and the performance of plasma Aβ 1-42 /Aβ 1-40 to detect cerebral amyloidosis was assessed using receiver operating characteristic analysis. We additionally investigated the correlations of plasma Aβ ratios with amyloid-PET and CSF Alzheimer's disease biomarkers, as well as platform agreement using Passing-Bablok regression and Bland-Altman analysis for both Aβ isoforms., Results: ELISA and SIMOA plasma Aβ 1-42 /Aβ 1-40 detected cerebral amyloidosis with identical accuracy (ELISA: area under curve (AUC) 0.78, 95% CI 0.72-0.84; SIMOA: AUC 0.79, 95% CI 0.73-0.85), and both increased the performance of a basic demographic model including only age and APOE-ε4 genotype (p ≤ 0.02). ELISA and SIMOA had positive predictive values of respectively 41% and 36% in cognitively normal elderly and negative predictive values all exceeding 88%. Plasma Aβ 1-42 /Aβ 1-40 correlated similarly with amyloid-PET for both platforms (Spearman ρ = - 0.32, p <  0.0001), yet correlations with CSF Aβ 1-42 /t-tau were stronger for ELISA (ρ = 0.41, p = 0.002) than for SIMOA (ρ = 0.29, p = 0.03). Plasma Aβ levels demonstrated poor agreement between ELISA and SIMOA with concentrations of both Aβ 1-42 and Aβ 1-40 measured by SIMOA consistently underestimating those measured by ELISA., Conclusions: ELISA and SIMOA demonstrated equivalent performances in detecting cerebral amyloidosis through plasma Aβ 1-42 /Aβ 1-40 , both with high negative predictive values, making them equally suitable non-invasive prescreening tools for clinical trials by reducing the number of necessary PET scans for clinical trial recruitment., Trial Registration: EudraCT 2009-014475-45 (registered on 23 Sept 2009) and EudraCT 2013-004671-12 (registered on 20 May 2014, https://www.clinicaltrialsregister.eu/ctr-search/trial/2013-004671-12/BE ).

Motor-, behavior- and/or cognition-related symptoms are key hallmarks in patients with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) with TDP-43 pathology (FTLD-TDP), respectively. It has been reported that these patients also experience sleep disturbances, which might implicate a disturbed circadian rhythm of the sleep/wake cycle. It remains unknown, however, whether cells involved in the circadian sleep/wake cycle are affected by ALS- and FTLD-related neuropathological changes including phosphorylated TDP-43 (pTDP-43) aggregates and dipeptide repeat protein (DPR) inclusions resulting from the C9orf72 hexanucleotide repeat expansion. Immunohistochemistry for DPR and pTDP-43 pathology was performed in post-mortem hypothalamus and pineal gland tissue of patients with ALS and/or FTLD-TDP with and without the C9orf72 repeat expansion and healthy controls. Circadian sleep/wake-associated cells, including pinealocytes and hypothalamic neurons related to the suprachiasmatic nucleus (SCN), were microscopically assessed. We observed numerous DPR inclusions (poly(GA), poly(GP), poly(GR) and poly(PR)) in the pinealocytes and few poly(GA) inclusions in the SCN-related neurons in C9orf72-related ALS and/or FTLD-TDP cases. These circadian sleep/wake-associated cells, however, were devoid of pTDP-43 pathology both in C9orf72- and nonC9orf72-related ALS and/or FTLD-TDP cases. Our neuropathological findings show that pinealocytes and, to a lesser extent, SCN-related neurons are affected by DPR pathology. This may reflect an involvement of these cells in sleep/wake disturbances observed in ALS and/or FTLD-TDP patients.

Purpose: Screening for paraneoplastic antibodies is often performed by means of indirect immunofluorescence on primate cerebellar slices. However, atypical immunofluorescence patterns, i.e. patterns that are not specifically related to paraneoplastic antibodies, are often reported. The clinical significance of these patterns is not clear. Therefore, the purpose of this study was to determine the significance and diagnostic value-in terms of a paraneoplastic neurological syndrome or other neurological disease being diagnosed in the patient-of such atypical immunofluorescence screening patterns on primate cerebellum., Methods: This study is a retrospective single center study including atypical indirect immunofluorescence screening patterns of patients with a negative or absent typing assay for intraneuronal and anti-amphiphysin paraneoplastic antibodies. Patients with a positive typing assay or without final diagnosis were excluded. Included patients were grouped according to (i) reported immunofluorescence pattern and (ii) established diagnosis, after which contingency table analyses were performed to investigate an interrelation between reported pattern and diagnostic group., Results: In 3.7% of cases, patients with an atypical pattern obtained a final diagnosis of a paraneoplastic neurological syndrome. The presence of atypical patterns was more prominent in patients with epilepsy or peripheral neuropathies ( p Monte Carlo simulation = 0.026), without, however, adding any diagnostic information., Conclusions: An atypical indirect immunofluorescence pattern on primate cerebellum in the screening for paraneoplastic antibodies has only very minor relevance with respect to paraneoplastic neurological syndromes or any other neurological disease, recommending clinicians to interpret the results of positive screening assays for such antibodies with care., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2019.)

Anti-GQ1b antibodies can be detected in the serum of patients with Miller Fisher syndrome (MFS) and its incomplete forms such as acute ophthalmoparesis (AO), acute ptosis, acute mydriasis, acute oropharyngeal palsy and acute ataxic neuropathy (AAN), as well as in pharyngeal-cervical-brachial weakness, Bickerstaff brainstem encephalitis (BBE) and in overlap syndromes with Guillain-Barré syndrome (MFS-GBS, BBE-GBS). We searched the laboratory medicine database at University Hospitals Leuven between 2002 and 2017 for serum samples with anti-GQ1b IgG antibodies. We identified eight patients with anti-GQ1b antibodies: 4 MFS, 2 AO, 1 MFS-GBS and 1 AAN. Mean age was 57 years and five patients were males. Preceding illness was present in all patients. At nadir, we observed most frequently gait disturbance, external ophthalmoplegia and absent/decreased reflexes. Albumino-cytological dissociation was present in four patients. Mean time between onset and nadir was 4 days, between onset and recovery 2.5 months. Five patients recovered completely and three had minor residual symptoms. Interestingly, one patient with AO experienced a second identical episode, approximately 1 year after the first one. Our data confirm the broad clinical spectrum associated with the presence of anti-GQ1b IgG antibodies. Incomplete MFS subtypes such as AO are a challenge for diagnosis, because of the limited (though invalidating) clinical presentation and the lack of confirming ancillary tests. Subacute onset of ophthalmoplegia and/or ataxia should urge the clinician to include the anti-GQ1b antibody syndrome in the differential diagnosis.

The lack of (inter-)laboratory standardization has hampered the application of universal cutoff values for Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers and their transfer to general clinical practice. The automation of the AD biomarker immunoassays is suggested to generate more robust results than using manual testing. Open-access platforms will facilitate the integration of automation for novel biomarkers, allowing the introduction of the protein profiling concept. A feasibility study was performed on an automated open-access platform of the commercial immunoassays for the 42-amino-acid isoform of amyloid-β (Aβ 1-42 ), Aβ 1-40 , and total tau in CSF. Automated Aβ 1-42 , Aβ 1-40 , and tau immunoassays were performed within predefined acceptance criteria for bias and imprecision. Similar accuracy was obtained for ready-to-use calibrators as for reconstituted lyophilized kit calibrators. When compared with the addition of a standard curve in each test run, the use of a master calibrator curve, determined before and applied to each batch analysis as the standard curve, yielded an acceptable overall bias of -2.6% and -0.9% for Aβ 1-42 and Aβ 1-40 , respectively, with an imprecision profile of 6.2% and 8.4%, respectively. Our findings show that transfer of commercial manual immunoassays to fully automated open-access platforms is feasible, as it performs according to universal acceptance criteria.

Objective: To examine neurofilament (Nf) concentrations according to symptom onset and clinical diagnostic certainty categories of amyotrophic lateral sclerosis (ALS)., Methods: We measured Nf light chain (NfL) and phosphorylated Nf heavy chain (pNfH) CSF and NfL serum levels in patients with ALS with first symptom onset ≤6 months (n = 54) or >6 months (n = 135) from sampling, and patients with other neurologic diseases, differential diagnoses of a motor neuron disease (MND mimics), and other MND variants to determine the diagnostic accuracy in patients with ALS with early symptom onset. Samples were received multicentric and analyzed by ELISA and Simoa platform and related to other clinical measures., Results: NfL and pNfH in CSF and NfL in serum were increased in early and later symptomatic phase ALS ( p < 0.0001). CSF and serum NfL and CSF pNfH discriminated patients with ALS with early symptom onset from those with other neurologic diseases and MND mimics with high sensitivity (94%, 88%, 98%, and 89%, 100%, 78%) and specificity (86%, 92%, 91%, and 94%, 90%, 98%) and did not vary between clinical diagnostic categories of ALS in the early symptomatic phase group. Baseline NfL and pNfH levels were not significantly different in patients with ALS with clinical progression to definite or probable ALS at follow-up., Conclusion: The measurement of Nf has potential to enhance diagnostic accuracy of ALS in those presenting soon after symptom onset, and is measurable across multiple centers., Classification of Evidence: This study provides Class II evidence that CSF and serum Nf concentrations discriminate ALS with early symptom onset from other neurologic diseases., (Copyright © 2017 American Academy of Neurology.)

Introduction: Disturbances of eye movements are infrequently encountered in motor neuron diseases (MNDs) or motor neuropathies, and there is no known syndrome that combines progressive muscle weakness with downbeat nystagmus., Methods: To describe the core clinical features of a syndrome of MND associated with downbeat nystagmus, clinical features were collected from 6 patients., Results: All patients had slowly progressive muscle weakness and wasting in combination with downbeat nystagmus, which was clinically most obvious in downward and lateral gaze. Onset was in the second to fourth decade with finger extension weakness, progressing to other distal and sometimes more proximal muscles. Visual complaints were not always present. Electrodiagnostic testing showed signs of regional motor axonal loss in all patients., Discussion: The etiology of this syndrome remains elusive. Because finger extension weakness and downbeat nystagmus are the discriminating clinical features of this MND, we propose the name FEWDON-MND syndrome. Muscle Nerve 56: 1164-1168, 2017., (© 2017 The Authors Muscle & Nerve Published by Wiley Periodicals, Inc.)

Background: Xenon has repeatedly been demonstrated to have only minimal hemodynamic side effects when compared to other anesthetics. Moreover, in experimental models, xenon was found to be neuroprotective and devoid of developmental neurotoxicity. These properties could render xenon attractive for the anesthesia in neonates and infants with congenital heart disease. However, experience with xenon anesthesia in children is scarce., Aims: We hypothesized that in children undergoing cardiac catheterization, general anesthesia with a combination of sevoflurane with xenon results in superior hemodynamic stability, compared to sevoflurane alone., Methods: In this prospective, randomized, single-blinded, controlled clinical trial, children with a median age of 12 [IQR 3-36] months undergoing diagnostic/interventional cardiac catheterization were randomized to either general anesthesia with 50-65vol% xenon plus sevoflurane or sevoflurane alone. The primary outcome was the incidence of intraprocedural hemodynamic instability, defined as the occurrence of: (i) a heart rate change >20% from baseline; or (ii) a change in mean arterial blood pressure >20% from baseline; or (iii) the requirement of vasopressors, inotropes, chronotropes, or fluid boluses. Secondary endpoints included recovery characteristics, feasibility criteria, and safety (incidence of emergence agitation and postoperative vomiting., Results: After inclusion of 40 children, the trial was stopped as an a priori planned blinded interim analysis revealed that the overall rate of hemodynamic instability did not differ between groups [100% in both the xenon-sevoflurane and the sevoflurane group. However, the adjuvant administration of xenon decreased vasopressor requirements, preserved better cerebral oxygen saturation, and resulted in a faster recovery. Xenon anesthesia was feasible (with no differences in the need for rescue anesthetics in both groups)., Conclusion: Our observations suggest that combining xenon with sevoflurane in preschool children is safe, feasible, and facilitates hemodynamic management. Larger and adequately powered clinical trials are warranted to investigate the impact of xenon on short- and long-term outcomes in pediatric anesthesia., (© 2017 John Wiley & Sons Ltd.)