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Current research efforts at neurological diseases have focused on identifying novel biomarkers to aid in diagnosis, to provide accurate prognostic information, and to monitor disease progression. This study presents the direct coupling of fiber-in-tube solid-phase microextraction to tandem mass spectrometry as a reliable method to determine amyloid beta peptides (Aβ38, Aβ40, and Aβ42) as biomarkers for Alzheimer's disease in cerebrospinal fluid (CSF) samples. To obtain the biocompatible fiber-in-tube SPME capillary, a PEEK tube segment was longitudinally packed with fine fibers [nitinol wires coated with a zwitterionic polymeric ionic liquid], to act as selective extraction medium. The fiber-in-tube SPME-MS/MS method integrated analyte extraction/enrichment and sample cleanup (exclusion of interferents) into one step. The method provided lower limits of quantification (LLOQ: 0.2 ng mL -1 for Aβ38 and 0.1 ng mL -1 for Aβ40 and Aβ42), high precision (CV lower than 11.6%), and high accuracy (relative standard deviation lower than 15.1%). This method was successfully applied to determine Aβ peptides in CSF samples obtained from AD patients (n = 8) and controls (healthy volunteers, n = 10). Results showed that Aβ42 levels in the CSF samples obtained from AD patients were significantly lower compared to healthy controls (p < 0.05). On the basis of the ROC analysis results, the Aβ42/Aβ40 ratio (AUC = 0.950, p < 0.01; 95%) performed significantly better than Aβ42 alone (AUC = 0.913, p < 0.01; 95%) in discriminating between AD patients and healthy controls and presented better diagnostic ability for AD. The novelties of this study are not only related to evaluating Aβ peptides as AD biomarkers, but also to demonstrating direct online coupling of fiber-in-tube SPME with MS/MS as a quantitative high-throughput method for bioanalysis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Little is known about the genetic basis of amyotrophic lateral sclerosis (ALS) outside Europe and US. In this study, we investigated whether intermediate CAG expansions at ATXN1 were associated to ALS in the Brazilian population. To accomplish that, representative samples from 411 unrelated patients and 436 neurologically normal controls from 6 centers spread over the territory were genotyped to quantify ATXN1 expansions. We found that ATXN1 intermediate-length expansion (≥34 CAG repeats) are associated with the disease (odds ratio = 2.19, 95% CI = 1.081-4.441, p = .026). Most ATXN1-positive patients had classical phenotype, but some of them presented predominant lower motor neuron involvement. None of them had associated ataxia. Frontotemporal dementia was concomitantly found in 12.5% of patients carrying the intermediate ATXN1 expansion. Further studies are needed to validate these findings and to understand the pathophysiological mechanisms that connect ataxin-1 and ALS., Competing Interests: Declaration of Competing Interest The authors report no conflict of interest regarding the current article., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Endocannabinoids (ECs) are endogenous lipid-based retrograde neurotransmitters that bind to cannabinoid receptors [cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2)]. Many ECs have been characterized; anandamide (AEA) and 2-arachidonoyl glycerol (2-AG) are still considered the primary ECs signaling mediators. Dysregulation of ECs has been implicated in a wide range of pathologies, including neurodegenerative diseases. Understanding how ECs participate in neurological diseases is important to describe the pathology and to establish new treatments. Considering the physicochemical properties of ECs, liquid chromatography coupled to tandem mass spectrometry has become the reference method to determine these endogenous substances, in trace levels, in different biological samples. This review describes the recent advances in LC-MS/MS methods designed to determine ECs in complex biological matrixes. The advantages, limitations, selectivity, matrix effect, and sensitivity associated with each approach are emphasized. This article comprises three sections: (I) sample preparation techniques (conventional, microextraction, and online systems), (II) chromatographic methods (especially LC-MS/MS), and (III) relationship between ECs levels and neurodegenerative diseases., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia characterized by the presence of a complex of signals resulting from the loss of REM sleep atony and manifested by vigorous and sometimes violent motor jerks and nocturnal vocalizations associated with dream enactment. RBD might be a clinical predictor of severity for Parkinson's disease (PD) and one of its most important non-motor manifestations, preceding the emergence of synucleinopathy by several years or even decades. The detection of RBD may represent a therapeutic window for research regarding the development of new neuroprotective therapies with the potential to modify the natural course of synucleinopathies, such as PD. We performed a scoping review of studies indexed in MEDLINE and LILACS focusing on pharmacological interventions for RBD associated with PD. Fourteen articles were selected. Study designs comprised randomized and non-randomized clinical trials (n = 153 participants) and observational studies (retrospective cohorts and case series, n = 248 participants). Melatonin and clonazepam appear to be useful for treating RBD in PD, but these findings are mostly supported by observational studies and a few controlled studies with a small number of participants. New pharmacological agents, such as melatoninergic agonists and phytocannabinoids, appear to be promising therapies. The findings from studies focusing on anticholinesterases and new dopaminergic agents are still deemed inconclusive., (Copyright © 2018. Published by Elsevier B.V.)

Intermediate-length cytosine-adenine-guanine nucleotide repeat expansions in the ATXN2 gene (which encodes for the protein Ataxin-2) have been linked to increased risk for amyotrophic lateral sclerosis (ALS) in different populations. There is no such study in the Brazilian population, which has a mixed ethnic background. We have thus selected 459 patients with ALS (372 Sporadic ALS and 87 Familial ALS) and 468 control subjects from 6 Brazilian centers to investigate this point. We performed polymerase chain reaction to determine the length of the ATXN2 alleles. Polymerase chain reaction products were resolved using capillary electrophoresis on ABI 3500 × l capillary sequencer. We found that ATXN2 intermediate-length expansions (larger than 26 repeats) were associated with an increased risk for ALS (odds ratio = 2.56, 95% confidence interval: 1.29-5.08, p = 0.005). Phenotype in patients with and without ATXN2 expansions was similar. Our findings support the hypothesis that ATXN2 plays an important role in the pathogenesis of ALS also in the Brazilian population., (Copyright © 2018 Elsevier Inc. All rights reserved.)

G 4 C 2 hexanucleotide repeat expansions in the C9orf72 gene seem to be the cause of numerous cases of amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia (FTD). In this study, we investigated the presence of the G 4 C 2 repeat expansion in 463 Brazilian probands, of whom 404 had ALS/motor neuron disease and 67 FTD, and in 63 healthy controls in the southeastern region of Brazil. The highest frequencies of the C9orf72 mutation were in the ALS-FTD group (50% of familial and 17.6% of sporadic cases), although it was also present in 5% of pure ALS/motor neuron disease patients (11.8% of familial and 3.6% of sporadic cases) and in 7.1% of pure familial FTD. Among G 4 C 2 repeat mutation carriers, 68.8% of the subjects who developed dementia symptoms were females. This frequency was significantly higher than the percentage reached by men with C9orf72 expansion who had this phenotype (p = 0.047). No abnormal repeat expansion was found in control groups. Inclusion of the C9orf72 genetic test in the molecular panels for Brazilian populations with these neurodegenerative diseases should be strongly considered., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Levodopa-induced dyskinesia (LID) is a common complication of advanced Parkinson's disease (PD). PD physiopathology is associated with dopaminergic and non-dopaminergic pathways, including the nitric oxide system. The present study aims to examine the association of a neuronal nitric oxide synthase gene (NOS1) single nucleotide polymorphism (rs2682826) with LID in PD patients., Methods and Results: We studied 186 PD patients using levodopa. The presence of LID was defined as a MDS-UPDRS Part IV score ≥1 on item 4.1. We tested for association between NOS1 rs2682826 and the presence, daily frequency, and functional impact of LID using regression models, adjusting for important covariates. There was no significant association between genotype and any of the LID-related variables examined., Conclusions: Our results suggest that this NOS1 polymorphism does not contribute to LID susceptibility or severity. However, additional studies that include a comprehensive set of NOS1 variants will be needed to fully define the role of this gene in LID., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: To evaluate the sensitivity and specificity of quantitative magnetic resonance (MR) iron mapping including R2, R2* and magnetic susceptibility to differentiate patients with Parkinson's disease (PD) from healthy controls., Materials and Methods: Thirty (30) healthy controls (HC) (64±7years old) and 20 patients with idiopathic PD (66±8years old) were studied using a 3T MR imaging scanner. R2 maps were generated from GRASE sequence while R2*, and quantitative susceptibility mapping (QSM) were obtained from a conventional multi-echo gradient-echo sequence. R2, R2* and relative susceptibility (Δχ) values of structures in the basal ganglia were measured for each patient and control. An analysis of sensitivity and specificity and unpaired t-test was applied to the two groups., Results: A significant difference (p<0.05) was found for R2 and ∆χ values in the substantia nigra as a whole and in the pars compacta for PD patients. The R2* values were different significantly (p<0.05) only on the substantia nigra pars compacta. QSM presented the highest sensitivity and specificity to differentiate the two populations., Conclusion: The QSM map was the most sensitive quantitative technique for detecting a significant increase of iron for PD. The highest significant difference between controls and patients was found in the substantia nigra pars compacta using QSM., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Autosomal dominant spinocerebellar ataxias (SCAs) are a clinical and genetically heterogeneous group of debilitating neurodegenerative diseases that are related to at least 36 different genetic loci; they are clinically characterized by progressive cerebellar ataxia and are frequently accompanied by other neurological and non-neurological manifestations. The relative frequency of SCA varies greatly among different regions, presumably because of a founder effect or local ethnicities. Between July 1998 and May 2012, we investigated 320 Brazilian patients with an SCA phenotype who belonged to 150 unrelated families with an autosomal dominant inheritance pattern and 23 sporadic patients from 13 Brazilian states. A total of 265 patients (82.8%) belonging to 131 unrelated families (87.3%) were found to have a definite mutation, and SCA3 accounted for most of the familial cases (70.7%), followed by SCA7 (6%), SCA1 (5.3%), SCA2 (2.7%), SCA6 (1.3%), SCA8 (0.7%) and SCA10 (0.7%). In the Ribeirão Preto mesoregion, which is located in the northeast part of São Paulo State, the prevalence of SCA3 was approximately 5 per 100,000 inhabitants, which is the highest prevalence found in Brazil. No mutation was found in the SCA12, SCA17 and DRPLA genes, and all the sporadic cases remained without a molecular diagnosis. This study further characterizes the spectrum of SCA mutations found in Brazilian patients, which suggests the existence of regional differences and demonstrates the expansion of the SCA8 locus in Brazilian families., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Recently, α-synuclein (α-syn) and DJ-1, 2 proteins critically involved in Parkinson's disease (PD), have been shown to be present in saliva, suggesting their potential utility as biomarkers of PD. However, the origin and influence of demographic characteristics (e.g., age or sex) on these proteins are unknown. We identified cheek epithelium, which forms the majority of the cellular component of saliva and is readily accessible clinically, as 1 of several potential sources of salivary α-syn and DJ-1. However, no PD-related trend in the cellular component was present. In the supernatant collected from 198 healthy subjects, no correlation was seen between salivary DJ-1 or α-syn with age. When male and female subjects were analyzed separately, a weak age-dependent increase in DJ-1 level was present in male subjects, along with slightly increased α-syn in female subjects. These results, albeit largely negative, provide critical information for understanding the salivary gland pathology and saliva as a PD biomarker source, and must be considered in future investigations of salivary changes in PD., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Social Anxiety Disorder (SAD) is more common among PD patients than in the general population. This association may be explained by psychosocial mechanisms but it is also possible that neurobiological mechanism underlying PD can predispose to SAD. The aim of this study was to investigate a possible dopaminergic mechanism involved in PD patients with SAD, by correlating striatal dopamine transporter binding potential (DAT-BP) with intensity of social anxiety symptoms in PD patients using SPECT with TRODAT-1 as the radiopharmaceutical. Eleven PD patients with generalized SAD and 21 PD patients without SAD were included in this study; groups were matched for age, gender, disease duration and disease severity. SAD diagnosis was determined according to DSM IV criteria assessed with SCID-I and social anxiety symptom severity with the Brief Social Phobia Scale (BSPS). Demographic and clinical data were also collected. DAT-BP was significantly correlated to scores on BSPS for right putamen (r=0.37, p=0.04), left putamen (r=0.43, p=0.02) and left caudate (r=0.39, p=0.03). No significant correlation was found for the right caudate (r=0.23, p=0.21). This finding may reinforce the hypothesis that dopaminergic dysfunction might be implicated in the pathogenesis of social anxiety in PD., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Reduction of visual acuity or of the contrast of the stimulus induces a prolongation of the pattern reversal visual evoked potential (PR-VEP) latencies, perhaps because these conditions cause deterioration of the visual capacity to recognize objects and may preferentially activate the slower central retina channel. The PR-VEP was obtained with a video stimulator and 3 kinds of stimuli: total video field, video with a central scotoma and a restricted central stimulus. The subjects were tested under conditions of normal (20/20) and reduced visual acuity (20/200) with 14' and 56' checks and 60% contrast, and under conditions of normal visual acuity (20/20) with 14' checks and with stimulus contrast of 60% and 25%. Blurring increased latencies and decreased amplitudes only with the 14' checks stimulus but no with 56' checks, and the amplitudes obtained with the central stimulus became greater than those obtained with a central scotoma. Reducing contrast increased only latency, and there was not difference between amplitudes obtained with a central stimulus or a central scotoma. We conclude that blurring small checks induces a preferential stimulation of receptors in the central retina, but the same effect was not observed when stimulus contrast was reduced.