Search

The objective of the present study was to evaluate the stability (-18°C) of minced African catfish (MF) for 180 days. Microbiological aspects, lipid oxidation, and total volatile nitrogenous bases (TVB-N) of the MF were determined with and without washing. Washing of the MF caused an increase in moisture content, decrease in proteins, and leaching of the compounds responsible for lipid oxidation. The TVB-N remained stable during the storage period. The microbiological parameters of the MF remained within the legal limits. Thus, a 180-days storage period does not affect the quality of MF and could be a good alternative for the exploitation of this species in Brazil. [ABSTRACT FROM AUTHOR]

Competing Interests: Competing interests: None declared.

Introduction: Neurosonology is a vital paraclinical investigation in modern neurology. However, access to education and certification in neurosonology for neurology residents and young specialists in Europe is challenging, and comprehensive data regarding this topic are scarce. Information regarding difficulties in neurosonology training across Europe may help bring this topic under the spotlight and act as a call for the harmonization of curricula across the continent., Methods: We performed an online survey targeting European neurology residents and young specialists, focusing on neurosonology training and certification. The survey was conducted between May and September 2023 and received responses from 282 participants representing 37 European countries., Results: There were disparities in neurosonology training during residency, with 6 (16.2%) out of 37 countries reporting a dedicated curriculum. The respondents expressed an overall lack of satisfaction with theoretical knowledge (rating their experience as very poor 28.0%, poor 20.2%, neutral 25.9%, good 19.3%, and very good 6.6%) and practical skills gained during their training (rating their experience as very poor 30.9%, poor 18.9%, neutral 22.6%, good 18.1%, and very good 9.5%). A total of 282 respondents (5.7%), 16 held a national certification in neurosonology, claiming obstacles such as high costs of certification and a limited number of certifying centers., Discussion: This survey reveals significant variations in neurosonology training across Europe, indicating difficulties in obtaining certification. Despite the increasing importance of neurosonology, many neurologists feel inadequately prepared and lack practical training during residency, emphasizing the need for better and more standardized access., Conclusion: The survey underscores challenges and disparities in neurosonology training and certification in Europe. Standardization of curricula and increased awareness about available certifications are crucial to address these issues. The interest in European Certification suggests a potential solution for enhancing neurosonology training at the international level., Competing Interests: Unrelated to this study AG-M has received speaker honoraria from TEVA and Altermedica. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Tiu, Durães, Di Lorenzo, Vashchenko, Gonzalez-Martinez, Accorroni, Carvalho, Sferruzza and Cuffaro.)

Background: Alzheimer's disease (AD) heritability is estimated to be around 70-80%. Yet, much of it remains to be explained. Studying transmission patterns may help in understanding other factors contributing to the development of AD., Objective: In this study, we aimed to search for evidence of autosomal recessive or X- and Y-linked inheritance of risk factors in a large cohort of Portuguese AD patients., Methods: We collected family history from patients with AD and cognitively healthy controls over 75 years of age. We compared the proportions of maternal and paternal history in male and female patients and controls (to search for evidence of X-linked and Y-linked inherited risk factors). We compared the risk of developing AD depending on parents' birthplace (same vs. different), as a proxy of remote consanguinity. We performed linear regressions to study the association of these variables with different endophenotypes., Results: We included 3090 participants, 2183 cognitively healthy controls and 907 patients with AD. Men whose mother had dementia have increased odds of developing AD comparing to women whose mother had dementia. In female patients with a CSF biomarker-supported diagnosis of AD, paternal history of dementia is associated with increased CSF phosphorylated Tau levels. People whose parents are from the same town have higher risk of dementia. In multivariate analysis, this proxy is associated with a lower age of onset and higher CSF phosphorylated tau., Conclusions: Our study gives evidence supporting an increased risk of developing AD associated with an X-linked inheritance pattern and remote consanguinity., (© 2024. The Author(s).)

Autonomous vehicles (AVs) rely heavily on sensors to perceive their surrounding environment and then make decisions and act on them. However, these sensors have weaknesses, and are prone to failure, resulting in decision errors by vehicle controllers that pose significant challenges to their safe operation. To mitigate sensor failures, it is necessary to understand how they occur and how they affect the vehicle's behavior so that fault-tolerant and fault-masking strategies can be applied. This survey covers 108 publications and presents an overview of the sensors used in AVs today, categorizes the sensor's failures that can occur, such as radar interferences, ambiguities detection, or camera image failures, and provides an overview of mitigation strategies such as sensor fusion, redundancy, and sensor calibration. It also provides insights into research areas critical to improving safety in the autonomous vehicle industry, so that new or more in-depth research may emerge.

Background: Pathogenic heterozygous mutations in the progranulin gene (GRN) are a key cause of frontotemporal dementia (FTD), leading to significantly reduced biofluid concentrations of the progranulin protein (PGRN). This has led to a number of ongoing therapeutic trials aiming to treat this form of FTD by increasing PGRN levels in mutation carriers. However, we currently lack a complete understanding of factors that affect PGRN levels and potential variation in measurement methods. Here, we aimed to address this gap in knowledge by systematically reviewing published literature on biofluid PGRN concentrations., Methods: Published data including biofluid PGRN concentration, age, sex, diagnosis and GRN mutation were collected for 7071 individuals from 75 publications. The majority of analyses (72%) had focused on plasma PGRN concentrations, with many of these (56%) measured with a single assay type (Adipogen) and so the influence of mutation type, age at onset, sex, and diagnosis were investigated in this subset of the data., Results: We established a plasma PGRN concentration cut-off between pathogenic mutation carriers and non-carriers of 74.8 ng/mL using the Adipogen assay based on 3301 individuals, with a CSF concentration cut-off of 3.43 ng/mL. Plasma PGRN concentration varied by GRN mutation type as well as by clinical diagnosis in those without a GRN mutation. Plasma PGRN concentration was significantly higher in women than men in GRN mutation carriers (p = 0.007) with a trend in non-carriers (p = 0.062), and there was a significant but weak positive correlation with age in both GRN mutation carriers and non-carriers. No significant association was seen with weight or with TMEM106B rs1990622 genotype. However, higher plasma PGRN levels were seen in those with the GRN rs5848 CC genotype in both GRN mutation carriers and non-carriers., Conclusions: These results further support the usefulness of PGRN concentration for the identification of the large majority of pathogenic mutations in the GRN gene. Furthermore, these results highlight the importance of considering additional factors, such as mutation type, sex and age when interpreting PGRN concentrations. This will be particularly important as we enter the era of trials for progranulin-associated FTD., (© 2024. The Author(s).)

Background: Familial cerebral cavernous malformations (FCCM) is a rare autosomal dominant disease, characterized by vascular malformations that can lead to macro and microhemorrhages. The neurocognitive impact of FCCM is still underrecognized., Methods: We report the clinical, neurocognitive, imaging and genetic data of a three generation family with FCCM., Results: A 63-year-old man (proband) had progressive memory impairment since the last year. Neurologic exam was unremarkable. Brain MRI showed multiple large cavernomas (mainly in the pons, left temporal, and right temporo-parietal) and scattered microhemorrhages. Neuropsychological assessment mainly revealed left frontal and right temporo-parietal dysfunction. A 41-year-old daughter, presented with headache, vertigo and memory complaints in the last 2 years. Neurological examination revealed left central facial paralysis. Brain MRI showed two small right parietal and internal capsule cavernomas, as well as microhemorrhages. Neuropsychological assessment showed moderate temporal neocortical left dysfunction. A 34-year-old daughter had recurrent headache and memory complaints, with unremarkable neurological exam. Brain MRI revealed two large cavernomas (left fronto-orbitary and inferior temporal), with few microhemorrhages. Neuropsychological assessment was normal. A granddaughter had mild headaches and a small right cerebellar cavernoma, without microhemorrhages. Neuropsychological assessment showed mild temporal neocortical left dysfunction. A nonsense variant, c.55C > T; p.R19* generating a premature stop codon in CCM2 gene shared by all affected family members was identified., Conclusions: Neuropsychological evaluation showed that memory complaints and cognitive impairment could be an important unrecognized finding in FCCM. Its pathophysiological mechanisms are still unknown but the role of recurrent microhemorrhages could provide an interesting hypothesis., (© 2023. The Author(s).)

In Portugal, heterozygous loss-of-function mutations in the progranulin ( GRN ) gene account for approximately half of the genetic mediated forms of frontotemporal dementia (FTD). GRN mutations reported thus far cause FTD through a haploinsufficiency disease mechanism. Herein, we aim to unveil the GRN mutation spectrum, investigated in 257 FTD patients and 19 family members from the central/north region of Portugal using sequencing methods. Seven different pathogenic variants were identified in 46 subjects including 40 patients (16%) and 6 relatives (32%). bvFTD was the most common clinical presentation among the GRN mutation patients, who showed a global pattern of moderate-to-severe frontotemporoparietal deficits in the neuropsychological evaluation. Interestingly, two mutations were novel (p.Thr238Profs*18, p.Leu354Profs*16), and five were previously described, although three of them only in the Portuguese population, suggesting a population-specific GRN mutational spectrum. The subjects harboring a GRN mutation showed a significant reduction in serum PGRN levels, supporting the pathogenic nature of these variants. This work broadens the mutation spectrum of GRN and the identification of the underlying GRN mutations provided an accurate genetic counselling and allowed the enrolment of subjects with GRN mutations (both asymptomatic and symptomatic) in ongoing clinical trials, which is essential to test new drugs for the disease.

Introduction: Mitochondrial oxidative phosphorylation (OXPHOS) diseases are challenging both from clinical and therapeutic perspectives. The advent of next-generation sequencing (NGS) boosted the discovery of new genetic defects affecting OXPHOS, with pathogenic variants identified in >350 genes to date [1]. However, in many patients, novel variants of unknown clinical significance are found. Subsequent functional studies may clarify its pathogenic consequences and modify the variant's classification, establishing a genetic diagnosis [2, 3]., Methods: Analysis of data obtained from patients (P1-P5) with novel genetic causes and functional genomics' studies performed, namely OXPHOS respiratory/glycolytic rates (Seahorse XF), enzymatic activity and assembly (BN-page), protein levels (SDS-WB), single muscle fiber assay, NGS and bioinformatics., Results/case Report: P1-Leigh syndrome (40y, male); Complex IV activity deficiency (full assembly absent), homozygous deletion (c.-11_13del, SURF1), not detected by NGS[2]. P2- Epileptic encephalopathy (8y, male); homozygous c.882-1G>A, FASTKD2; OXPHOS decrease; reduced FASTKD2 expression and abnormal respiratory/glycolytic rates. P3-Cardiomyopathy/ nephropathy (39y, male); c.29G>C, FASTKD2; OXPHOS decrease; reduced FASTKD2 levels. P4-CPEO (62y, female); multiple OXPHOS deficiency; mtDNA alterations (m.7486G>A, MTTS1; 4,977bp del); higher levels of mutant mtDNA alterations in COX-deficient fibers [3]. P5- Polyneuropathy (15y, female); heterozygous c.1437C>A, POLG; combined def. or normal OXPHOS activity/respiratory capacity (tissue variable), raised CI assembly; normal POLG levels. Also, proteins' expression levels were reduced (P1-4), confirming pathogenicity. In P5, data do not support pathogenicity., Conclusion: If specific functional results are similar to controls, one might inquire about the pathogenicity of the studied variant and more genetic or bioinformatics analyses and family investigations are needed. There are also limitations of NGS in mutation detection that Sanger sequencing can overcome (P1). When performed first, the OXPHOS activity may guide to genetic screening or interpretation, concordant to later assembly results. All cases were solved and data may be crucial for genetic counseling., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Zellweger spectrum disorder (ZSD) (OMIM#214100) is a phenotypic continuum ranging from severe to mild presentations. ZSD is now used in all individuals with a defect in one of the 13 ZSD-PEX genes, regardless of phenotype. Diagnosis can be suggested by abnormal levels of very long-chain fatty acids, phytanic acid, pristanic acid, plasmalogens, pipecolic acid, or bile acids. However, false negatives are frequent, mostly in older patients. Definite diagnosis is established in a proband with suggestive clinical findings by identification of biallelic pathogenic variants in one of the 13 ZSD-PEX genes., Case Report: A 39-year-old female patient had a global development delay since her first year of life. Never developed oral language but had sphincter control and was able to walk and laugh. At 8 years old, she had her first seizure and lost sphincter control when she was 20 years old. At 28 years old, she had an episode of status epilepticus, with severe prostration and became bedridden. She is currently mute, without capacity for communication or motor control. She has no consanguineous parents, has a 35 year old brother with global developmental delay and their mother had a history of an abortion, without other relevant family history. Brain MRI of the patient revealed severe leukodystrophy mainly periventricular, bilateral and symmetric, and less prominent in the cerebellar white matter, with severe cerebral and corpus callosum atrophy. Molecular study with a leukodystrophy gene panela identified a homozygotic pathogenic variant on PEX 1 gene (NM_000466.3) - c.2528G>A (p.(Gly843Asp)), confirming the diagnosis of ZSD., Conclusion: Homozygosity for PEX1 p.Gly843Asp seems to be associated with an intermediate/milder ZSD phenotype,with survival until adulthood. Some patients develop progressive degeneration of CNS myelin, a leukodystrophy pattern, like this patient, which may lead to regression. This girl with ZSD had a rapid and severe loss of previous skills after a seizure. Even though there is no specific treatment for this disease, a correct diagnosiswas very important for the parents and for family genetic counselling., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Physical activity and exercise have been suggested as effective interventions for the prevention and management of mild cognitive impairment (MCI) and dementia, but there are no international guidelines., Objectives: To create a set of evidence- and expert consensus-based prevention and management recommendations regarding physical activity (any bodily movement produced by skeletal muscles that results in energy expenditure) and exercise (a subset of physical activity that is planned, structured, repetitive), applicable to a range of individuals from healthy older adults to those with MCI/dementia., Methods: Guideline content was developed with input from several scientific and lay representatives' societies. A systematic search across multidisciplinary databases was carried out until October 2021. Recommendations for prevention and management were developed according to the GRADE and complemented by consensus statements from the expert panels., Recommendations: Physical activity may be considered for the primary prevention of dementia. In people with MCI there is continued uncertainty about the role of physical activity in slowing the conversion to dementia. Mind-body interventions have the greatest supporting evidence. In people with moderate dementia, exercise may be used for maintaining disability and cognition. All these recommendations were based on a very low/low certainty of evidence., Conclusions: Although the scientific evidence on the beneficial role of physical activity and exercise in preserving cognitive functions in subjects with normal cognition, MCI or dementia is inconclusive, this panel, composed of scientific societies and other stakeholders, recommends their implementation based on their beneficial effects on almost all facets of health., (© 2023. The Author(s).)

Introduction - SERAC1 deficiency phenotype range from MEGD(H)EL syndrome, the most severe, to juvenile complicated spastic paraplegia, to adult-onset dystonic features (in only one patient). The MEGD(H)EL syndrome is characterized by (3-methylglutaconic aciduria with deafness-dystonia, [hepatopathy], encephalopathy, and Leigh-like syndrome). Biochemical abnormalities: elevated urinary 3 - metilglutaconic and 3-metilglutaric acids, high lactate and alanine in serum. Diagnosis is confirmed when biallelic pathogenic variants in SERAC1 gene are found. Brain MRI: basal ganglia lesions and generalized atrophy. Results/Case report - A 30-year-old patient with a moderate intellectual disability, developed, since the age of 25, a progressive loss of previous capacities (hand dexterity, oral language), and later subacute generalized dystonic features. Currently he has spastic tetraparesis, dystonia, scoliosis and autistic behavior, with bilateral basal ganglia lesions on brain MRI. Genetic study revealed biallelic pathogenic variants in SERAC1 gene, confirm MEGD(H)EL. A 73 years old patient with cognitive impairment and progressive spastic tetraparesis had multiple periventricular T2 hyperintense lesions. She has a homozygotic SERAC1 variant NM_032861: exon4:c.T139A: p.F471 (rs112780453), considered benign. Biochemical study revealed elevated plasmatic alanine and urinary3-metilglutaconic and 3-metilglutaric acid. This profile is concordant with mitochondrial dysfunction and SERAC1 Deficit. Conclusion - The first patient has the clinical symptoms associated to the MEGD(H)EL syndrome, and the biochemical and genetic confirmation of the diagnosis, without reservations. However, in the second patient, the progressive paraparesis and cognitive impairment did not appear to be caused by multiple sclerosis nor subcortical vascular leukoencephalopathy (without vascular risk factors). The abnormal biochemical profile is suggestive of SERAC1 Deficiency, even without genetic confirmation. In what should we believe?, (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Leukodystrophy with vanishing white matter (LVWM) is an autosomal recessive disease with typical pediatric-onset caused by mutations in one of the five EIF2B genes. Adult-onset (AO) cases are rare., Methods: In this observational study, we reviewed clinical and laboratory information of the patients with AO-LVWM assessed at two referral centers in Italy and Portugal from Jan-2007 to Dec-2019., Results: We identified 18 patients (13 females) with AO-LVWM caused by EIF2B5 or EIF2B3 mutations. Age of neurological onset ranged from 16 to 60 years, with follow-ups occurring from 2 to 37 years. Crucial symptoms were cognitive and motor decline. In three patients, stroke-like events were the first manifestation; in another, bladder dysfunction remained the main complaint across decades. Brain MRI showed white matter (WM) rarefaction in all cases, except two. Diffusion-weighted imaging documented focal hyperintensity in the acute stage of stroke-like events. 1 H-spectroscopy primarily showed N-acetyl-aspartate reduction; 18 fluorodeoxyglucose-PET revealed predominant frontoparietal hypometabolism; evoked potential studies demonstrated normal-to-reduced amplitudes; neuro-ophthalmological assessment showed neuroretinal thinning, and b-wave reduction on full-field electroretinogram. Interestingly, we found an additional patient with LVWM-compatible phenotype and monoallelic variants in two distinct eIF2B genes, EIF2B1 and EIF2B2., Conclusions: AO-LVWM presents varying clinical manifestations at onset, including stroke-like events. WM rarefaction is the most consistent diagnostic clue even in the latest onset cases. Spectroscopy and electrophysiological features are compatible with axon, rather than myelin, damage. Cerebral glucose metabolic abnormalities and retinal alterations can be present. LVWM might also be caused by a digenic inheritance affecting the eIF2B complex., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background and Purpose: Blood-based biomarkers are promising tools for the diagnosis of Alzheimer disease (AD) at prodromal stages (mild cognitive impairment [MCI]) and are hoped to be implemented as screening tools for patients with cognitive complaints. In this work, we evaluated the potential of peripheral neurological biomarkers to predict progression to AD dementia and the relation between blood and cerebrospinal fluid (CSF) AD markers in MCI patients referred from a general neurological department., Methods: A group of 106 MCI patients followed at the Neurology Department of Coimbra University Hospital was included. Data regarding baseline neuropsychological evaluation, CSF levels of amyloid β 42 (Aβ42), Aβ40, total tau (t-Tau), and phosphorylated tau 181 (p-Tau181) were available for all the patients. Aβ42, Aβ40, t-Tau, p-Tau181, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) levels were determined in baseline stored serum and plasma samples by commercial SiMoA (Single Molecule Array) assays. Progression from MCI to AD dementia was assessed at follow-up (mean = 5.8 ± 3.4 years)., Results: At baseline, blood markers NfL, GFAP, and p-Tau181 were significantly increased in patients who progressed to AD at follow-up (p < 0.001). In contrast, plasma Aβ42/40 ratio and t-Tau showed no significant differences between groups. NfL, GFAP, and p-Tau181 demonstrated good diagnostic accuracy to identify progression to AD dementia (area under the curve [AUC] = 0.81, 0.80, and 0.76, respectively), which improved when combined (AUC = 0.89). GFAP and p-Tau181 were correlated with CSF Aβ42. Association of p-Tau181 with NfL was mediated by GFAP, with a significant indirect association of 88% of the total effect., Conclusions: Our findings highlight the potential of combining blood-based GFAP, NfL, and p-Tau181 to be applied as a prognostic tool in MCI., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Complexity is the key element of software quality. This article investigates the problem of measuring code complexity and discusses the results of a controlled experiment to compare different views and methods to measure code complexity. Participants (27 programmers) were asked to read and (try to) understand a set of programs, while the complexity of such programs is assessed through different methods and perspectives: (a) classic code complexity metrics such as McCabe and Halstead metrics, (b) cognitive complexity metrics based on scored code constructs, (c) cognitive complexity metrics from state-of-the-art tools such as SonarQube, (d) human-centered metrics relying on the direct assessment of programmers' behavioral features (e.g., reading time, and revisits) using eye tracking, and (e) cognitive load/mental effort assessed using electroencephalography (EEG). The human-centered perspective was complemented by the subjective evaluation of participants on the mental effort required to understand the programs using the NASA Task Load Index (TLX). Additionally, the evaluation of the code complexity is measured at both the program level and, whenever possible, at the very low level of code constructs/code regions, to identify the actual code elements and the code context that may trigger a complexity surge in the programmers' perception of code comprehension difficulty. The programmers' cognitive load measured using EEG was used as a reference to evaluate how the different metrics can express the (human) difficulty in comprehending the code. Extensive experimental results show that popular metrics such as V(g) and the complexity metric from SonarSource tools deviate considerably from the programmers' perception of code complexity and often do not show the expected monotonic behavior. The article summarizes the findings in a set of guidelines to improve existing code complexity metrics, particularly state-of-the-art metrics such as cognitive complexity from SonarSource tools., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Hao, Hijazi, Durães, Medeiros, Couceiro, Lam, Teixeira, Castelhano, Castelo Branco, Carvalho and Madeira.)

Serum light-chain neurofilaments (sNfL) have been investigated as a potential minimally invasive biomarker that could help in the diagnosis of patients with cognitive symptoms. We assessed the correlation between sNfL and cerebrospinal fluid (CSF) biomarkers (sNfL versus CSF NfL, ρ= 0.70, p < 0.001), the performance of sNfL in distinguishing controls from patients (controls versus frontotemporal dementia, area under curve 0.86), and sNfL differences in mild cognitive impairment according to amyloid-β (Aβ) deposition (Aβ versus non-Aβ, p = 0.017). Our results support the role of this biomarker in the screening and risk stratification of patients followed in a neurological consultation of a tertiary center.

Background: Frontal-variant of Alzheimer's disease (fvAD) was purposed for patients with AD pathology that, despite the typical amnestic presentation, show early and progressive deterioration of behavior and executive functions, closely resembling the behavioral-variant of frontotemporal dementia (bvFTD). This leads to a challenging differential diagnosis where neuropsychological evaluation and in vivo pathological evidence are essential., Objective: To evaluate the contribution of a comprehensive neuropsychological assessment (NP) battery in distinguishing between fvAD-dementia and bvFTD supported by cerebrospinal fluid (CSF) biomarkers., Methods: We included 40 patients with a baseline NP profile with prominent early executive and/or behavioral dysfunction, who meet both diagnosis of bvFTD and fvAD-dementia, according to international criteria. All patients underwent comprehensive NP assessment and CSF-AD biomarker evaluation. Neuropsychological domains as well as clinical and sociodemographic features, and APOE genotype were compared between groups., Results: 21 patients (52.5%) met the biological criteria for AD (decreased Aβ42 together with increased T-tau or P-tau in CSF) and were therefore classified as fvAD (mean age was 64.57, with 47.6% female). There were no differences between groups regarding age/age-at-onset, gender, or educational level. Regarding neuropsychological profile, performances in language and memory functions were equivalent in both groups. Significant differences were found in visuo-constructional abilities (p = 0.004), Trail Making Test A (p < 0.001), and Raven's Colored Progressive Matrices (p = 0.019), with fvAD patients showing worst performances., Conclusion: In patients with an early prominent frontal profile, a higher impairment in attention and visuo-spatial functions, signaling additional right hemisphere fronto-parietal dysfunction, point towards a diagnosis of fvAD-dementia and may be useful in clinical practice.

Background: Mild cognitive impairment (MCI) is considered a prodromal state of dementia. Abnormal values of cerebrospinal fluid Alzheimer's disease biomarkers (CSF-AD-b) have been associated with a higher risk of conversion to dementia (due to Alzheimer's disease), but studies evaluating the ability of Montreal Cognitive Assessment (MoCA) in this task are lacking., Objective: This study aims to investigate the relationship between MoCA and CSF-AD-b, as well as the ability of those tools to predict conversion to dementia., Methods: Taking advantage of our MCI cohort with biological characterization on longitudinal follow-up (180 patients followed for 62.6 months during which 41.3% converted), we computed MoCA and MMSE z-scores, using Portuguese normative data. The performance in MoCA z-score was correlated with CSF-AD-b and the relative time to conversion and risk according to baseline characteristics were analyzed using Kaplan-Meier analysis and Cox regression models., Results: MoCA z-scores were correlated with Aβ42 (p = 0.026), t-tau (p = 0.033), and p-tau (p = 0.01). Impaired MMSE (p < 0.001) and MoCA z-scores (p = 0.019), decreased Aβ42 (p < 0.001) and increased t-tau (p < 0.001) and p-tau (p < 0.001) were associated with shorter estimated time of conversion. Aβ42 (p < 0.001) and MMSE z-scores (p = 0.029) were independent predictors of conversion. For those with at least 9 years of education, MoCA z-score (p = 0.004) (but not MMSE) was an independent predictor of conversion as well as Aβ42., Conclusions: This study confirms the role of CSF-AD-b, namely Aβ42, in predicting conversion from MCI to dementia and suggests the utility of MoCA in predicting conversion in highly educated subjects, supporting its use in the evaluation of MCI patients.

Introduction: The CDR Dementia Staging Instrument PLUS National Alzheimer's Coordinating Center (CDR plus NACC FTLD) was developed by adding to the standard CDR two extra domains focused on the main features of frontotemporal lobar degeneration (FTLD): language and behavior/personality. We intended to perform the validation studies for the European-Portuguese population., Methods: A total of 105 participants matched for age, education, and disease staging (35 bvFTD, 35 AD, and 35 controls) were included. A translated-version of the CDR and the two added domains was administered by a neuropsychologist who was blinded to the diagnosis., Results: The bvFTD group had higher baseline CDR plus NACC FTLD scores compared to the AD and controls. Only the sum-of-boxes (SB) score, the behavior/personality, and language domains were able to distinguish between clinical groups. Logistic regression analyses showed that adding the behavior/personality domain with or without language significantly enhanced the discriminating ability., Discussion: Results show that the CDR plus NACC FTLD is a reliable tool in the diagnostic process of bvFTD patients and has an added value in distinguishing them from patients with AD., Competing Interests: Dr. Knopman serves on a Data Safety Monitoring Board for the DIAN study. He served on a Data Safety Monitoring Board for a tau therapeutic for Biogen but received no personal compensation. He is an investigator in clinical trials sponsored by Biogen, Lilly Pharmaceuticals, and the University of Southern California. He has served as a consultant for Roche, Samus Therapeutics, Magellan Health, and Alzeca Biosciences but receives no personal compensation. He receives funding from the National Institutes of Health (NIH). The remaining authors have nothing to disclose. , (© 2022 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Undernutrition remains a major issue in global health. Low protein-energy consumption, results in stunting, wasting and/or underweight, three deleterious forms of malnutrition that affect roughly 200 million children under the age of five years. Undernutrition compromises the immune system with the generation of various degrees of immunodeficiency, which in turn, renders undernourished individuals more sensitive to acute infections. The severity of various infectious diseases including visceral leishmaniasis (VL), influenza, and tuberculosis is associated with undernutrition. Immunosuppression resulting from protein-energy undernutrition severely impacts primary and secondary lymphoid organs involved in the response to related pathogens. The thymus-a primary lymphoid organ responsible for the generation of T lymphocytes-is particularly compromised by both undernutrition and infectious diseases. In this respect, we will discuss herein various intrathymic cellular and molecular interactions seen in undernutrition alone or in combination with acute infections. Many examples illustrated in studies on humans and experimental animals clearly revealed that protein-related undernutrition causes thymic atrophy, with cortical thymocyte depletion. Moreover, the non-lymphoid microenvironmental compartment of the organ undergoes important changes in thymic epithelial cells, including their secretory products such as hormones and extracellular matrix proteins. Of note, deficiencies in vitamins and trace elements also induce thymic atrophy. Interestingly, among the molecular interactions involved in the control of undernutrition-induced thymic atrophy is a hormonal imbalance with a rise in glucocorticoids and a decrease in leptin serum levels. Undernutrition also yields a negative impact of acute infections upon the thymus, frequently with the intrathymic detection of pathogens or their antigens. For instance, undernourished mice infected with Leishmania infantum (that causes VL) undergo drastic thymic atrophy, with significant reduction in thymocyte numbers, and decreased levels of intrathymic chemokines and cytokines, indicating that both lymphoid and microenvironmental compartments of the organ are affected. Lastly, recent data revealed that some probiotic bacteria or probiotic fermented milks improve the thymus status in a model of malnutrition, thus raising a new field for investigation, namely the thymus-gut connection, indicating that probiotics can be envisioned as a further adjuvant therapy in the control of thymic changes in undernutrition accompanied or not by infection., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Savino, Durães, Maldonado-Galdeano, Perdigon, Mendes-da-Cruz and Cuervo.)

Ultra-short-term HRV features assess minor autonomous nervous system variations such as variations resulting from cognitive stress peaks during demanding tasks. Several studies compare ultra-short-term and short-term HRV measurements to investigate their reliability. However, existing experiments are conducted in low cognitively demanding environments. In this paper, we propose to evaluate these measurements' reliability under cognitively demanding tasks using a near real-life setting. For this purpose, we selected 31 HRV features, extracted from data collected from 21 programmers performing code comprehension, and compared them across 18 different time frames, ranging from 3 min to 10 s. Statistical significance and correlation tests were performed between the features extracted using the larger window (3 min) and the same features extracted with the other 17 time frames. We paired these analyses with Bland-Altman plots to inspect how the extraction window size affects the HRV features. The main results show 13 features that presented at least 50% correlation when using 60-second windows. The HF and mNN features achieved around 50% correlation using a 30-second window. The 30-second window was the smallest time frame considered to have reliable measurements. Furthermore, the mNN feature proved to be quite robust to the shortening of the time resolution.

Introduction: Several neuroimmunological disorders have distinct phenotypes according to the age of onset, as in multiple sclerosis or myasthenia gravis. It is also described that late onset NMOSD (LONMOSD) has a different phenotype., Objective: To describe the clinical/demographic characteristics of the LONMOSD and distinguish them from those with early onset (EONMOSD)., Methods: From a nationwide Portuguese NMOSD study we analyzed the clinical/demographic characteristics of the LONMOSD., Results: From the 180 Portuguese patients 45 had disease onset after 50 years old, 80% were female. 23 had anti-AQP4 antibodies (51.1%), 13 anti-MOG antibodies (28.9%) and 9 were double seronegative (20.0%). The most common presenting phenotypes in LONMOSD were transverse myelitis (53.3%) and optic neuritis (26.7%), without difference from EONMOSD (p = 0.074). The mean EDSS for LONMOSD was 6.0 (SD=2.8), after a mean follow-up time of 4.58 (SD=4.47) years, which was significantly greater than the mean EDSS of EONMOSD (3.25, SD=1.80)(p = 0.022). Anti-AQP4 antibodies positive LONMOSD patients had increased disability compared to anti-MOG antibodies positive LONMOSD (p = 0.022). The survival analysis showed a reduced time to use a cane for LONMOSD, irrespective of serostatus (p<0.001)., Conclusions: LONMOSD has increased disability and faster progression, despite no differences in the presenting clinical phenotype were seen in our cohort., (Copyright © 2022. Published by Elsevier B.V.)

Background and Purpose: TP73 was recently reported to cause amyotrophic lateral sclerosis (ALS). ALS and frontotemporal dementia (FTD) are considered to form part of a continuum. We aimed to investigate whether TP73 variants may be associated with FTD., Methods: We studied a thoroughly investigated cohort of 65 Portuguese patients with frontotemporal dementia using whole-exome sequencing. The patients had no other known genetic cause for their disease (C9orf72 expansion was also excluded)., Results: Of the 65 patients studied, two had rare variants in TP73 (p.Gly605Ser and p.Arg347Trp). Both variants had minor allele frequency <0.001 and were predicted to be pathogenic in silico. The two patients displayed a phenotype that included predominant language impairment, suggestive of non-fluent progressive aphasia., Conclusion: We show that two thoroughly studied patients without other known genetic changes harbored TP73 rare variants, which are pathogenic in silico. This adds evidence to support the role of TP73 in the ALS-FTD spectrum, especially in primary progressive aphasia cases., (© 2022 European Academy of Neurology.)

Background: Lewy bodies are a hallmark of Dementia with Lewy Bodies. They can also be found in the sinoatrial node and may be associated with heart disease., Objectives: We aimed to investigate a possible association between Lewy Body dementia and atrial fibrillation., Methods: We performed a case-control study based on our centre's cohort of degenerative dementia (Dementia with Lewy Bodies and Alzheimer's disease) patients. The possible association between Lewy Body dementia and atrial fibrillation was studied through a binomial logistic regression, which adjusted for comorbidity data., Results: We included 461 patients. 45 of the 398 (11.3%) with Alzheimer's disease and 14 of the 63 with Dementia with Lewy Bodies (22.2%) had atrial fibrillation. Heart failure (OR = 3.345, 95%CI = [1.618, 6.916], p = 0.001), hypertension (OR = 2.547, 95%CI = [1,137, 5.703], p = 0.023), stroke (OR = 2.274, 95%CI = [1.013, 5.103], p = 0.046) and Dementia with Lewy Bodies (OR = 2.536, 95%CI = [1.105, 5.822], p = 0.028) were associated with atrial fibrillation., Conclusions: We found an association between Dementia with Lewy bodies and Atrial Fibrillation., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background and Purpose: Neurofilament light chain (NfL) has recently been proposed as a promising biomarker in frontotemporal dementia (FTD). We investigated the correlation of both cerebrospinal fluid (CSF) and serum NfL with detailed neuropsychological data and cognitive decline in a cohort of sporadic and familial FTD., Methods: CSF and serum NfL, as well as conventional CSF Alzheimer's disease (AD) biomarkers (Aβ42, t-Tau, p-Tau181), were determined in 63 FTD patients (30 sporadic-FTD, 20 with progranulin (GRN) mutations [FTD-GRN], 13 with chromosome 9 open reading frame 72 [C9orf72] expansions [C9orf72-FTD]), 37 AD patients, and 31 neurologic controls. Serum NfL was also quantified in 37 healthy individuals. Correlations between baseline CSF and serum NfL levels, standardized neuropsychological tests, and the rate of cognitive decline in FTD patients were assessed., Results: CSF and serum NfL presented with significantly higher levels in FTD than in AD patients and both control groups. Within FTD subtypes, genetic cases, and particularly FTD-GRN, had higher CSF and serum NfL levels. Significant correlations between NfL levels and overall cognitive function, abstract reasoning (CSF and serum), executive functions, memory, and language (serum) were found. A relationship between increased baseline CSF and serum NfL and a decay in cognitive performance over time was also observed., Conclusions: Our findings highlight the potential of serum NfL as a useful surrogate end point of disease severity in upcoming targeted treatments., (© 2021 European Academy of Neurology.)

Background: The ATN scheme was proposed as an unbiased biological characterization of the Alzheimer's disease (AD) spectrum, grouping biomarkers into three categories: brain Amyloidosis-A, Tauopathy-T, Neurodegeneration-N. Although this scheme was mainly recommended for research, it is relevant for diagnosis., Objective: To evaluate the ATN scheme performance in real-life cohorts reflecting the inflow of patients with cognitive complaints and different underlying disorders in general neurological centers., Methods: We included patients (n = 1,128) from six centers with their core cerebrospinal fluid-AD biomarkers analyzed centrally. A was assessed through Aβ42/Aβ40, T through pTau-181, and N through tTau. Association between demographic features, clinical diagnosis at baseline/follow-up and ATN profiles was assessed., Results: The prevalence of ATN categories was: A-T-N-: 28.3%; AD continuum (A + T-/+N-/+): 47.8%; non-AD (A- plus T or/and N+): 23.9%. ATN profiles prevalence was strongly influenced by age, showing differences according to gender, APOE genotype, and cognitive status. At baseline, 74.6% of patients classified as AD fell in the AD continuum, decreasing to 47.4% in mild cognitive impairment and 42.3% in other neurodegenerative conditions. At follow-up, 41% of patients changed diagnosis, and 92% of patients that changed to AD were classified within the AD continuum. A + was the best individual marker for predicting a final AD diagnosis, and the combinations A + T+ (irrespective of N) and A + T+N+ had the highest overall accuracy (83%)., Conclusion: The ATN scheme is useful to guide AD diagnosis in real-life neurological centers settings. However, it shows a lack of accuracy for patients with other types of dementia. In such cases, the inclusion of other markers specific for non-AD proteinopathies could be an important aid to the differential diagnosis.

Introduction: Neuromyelitis optica spectrum disorder (NMOSD) is a rare disorder in which astrocyte damage and/or demyelination often cause severe neurological deficits., Objective: To identify Portuguese patients with NMOSD and assess their epidemiological/clinical characteristics., Methods: This was a nationwide multicenter study. Twenty-four Portuguese adult and 3 neuropediatric centers following NMOSD patients were included., Results: A total of 180 patients met the 2015 Wingerchuk NMOSD criteria, 77 were AQP4-antibody positive (Abs+), 67 MOG-Abs+, and 36 seronegative. Point prevalence on December 31, 2018 was 1.71/100,000 for NMOSD, 0.71/100,000 for AQP4-Abs+, 0.65/100,000 for MOG-Abs+, and 0.35/100,000 for seronegative NMOSD. A total of 44 new NMOSD cases were identified during the two-year study period (11 AQP4-Abs+, 27 MOG-Abs+, and 6 seronegative). The annual incidence rate in that period was 0.21/100,000 person-years for NMOSD, 0.05/100,000 for AQP4-Abs+, 0.13/100,000 for MOG-Abs+, and 0.03/100,000 for seronegative NMOSD. AQP4-Abs+ predominated in females and was associated with autoimmune disorders. Frequently presented with myelitis. Area postrema syndrome was exclusive of this subtype, and associated with higher morbidity/mortality than other forms of NMOSD. MOG-Ab+ more often presented with optic neuritis, required less immunosuppression, and had better outcome., Conclusion: Epidemiological/clinical NMOSD profiles in the Portuguese population are similar to other European countries., (Copyright © 2021. Published by Elsevier B.V.)

Malnutrition is a risk factor for developing visceral leishmaniasis and its severe forms. Our group demonstrated that malnourished animals infected with Leishmania infantum had severe atrophies in lymphoid organs and T cell subpopulations as well as altered levels of thymic and splenic chemotactic factors, all of which resulted in dysfunctional lymphoid microenvironments that promoted parasite proliferation. Here, we hypothesize that malnutrition preceding parasite infection leads to structural and immunological changes in the gut mucosae, resulting in a failure in the immune response sensed in the intestine. To evaluate this, we analyzed the immunopathological events resulting from protein malnutrition in the guts of BALB/c mice infected with L. infantum . We observed lymphocytic/lymphoplasmacytic inflammatory infiltrates and lymphoid hyperplasia in the duodenum of well-nourished-infected mice; such alterations were worsened when malnutrition preceded infection. Parasite infection induced a significant increase of duodenal immunoglobulin A (IgA) of well-nourished animals, but those levels were significantly decreased in malnourished-infected mice. In addition, increased levels of Th17-related cytokines in duodenums of malnourished animals supported local inflammation. Together, our results suggest that the gut plays a potential role in responses to L. infantum infection-and that such responses are impaired in malnourished individuals.

The distinction between sporadic and genetic behavioural-variant frontotemporal dementia (bvFTD) regarding some neuropsychological (NP) features remains challenging. Specifically, progranulin (GRN)-associated bvFTD frequently presents with early episodic memory impairment and some degree of parietal dysfunction which are supporters of Alzheimer's disease (AD) diagnosis. In this context, we aimed to characterize the NP profile of GRN-bvFTD as compared to sporadic-bvFTD and AD in patients with mild dementia (Mini-Mental State Examination score ≥ 17 and Clinical Dementia Rating Scale score ≤ 1. We identified 21 patients at Centro Hospitalar e Universitário de Coimbra, Portugal with GRN mutations belonging to fifteen different families. As our focus was bvFTD variants, FTD-related aphasic forms (3 patients) were excluded. The remaining 18 GRN-bvFTD were further matched with 18 sporadic-bvFTD and 18 AD patients according to disease staging, age and education. All patients completed the Mini-Mental State Examination, Montreal Cognitive Assessment (MoCA) and a comprehensive NP assessment battery. Results were converted into z-scores. Differences between groups in individual NP measures and NP domains were assessed through non-parametric tests (Kruskal-Wallis test analysis) and eta squared (ŋ 2 ) was calculated as a measure of effect size. Group comparisons show that GRN patients have worse performances on verbal retrieval processes (P = 0.039, ŋ 2 = 0.110) and visuoconstructive abilities (P = 0.039, ŋ 2 = 0.190) than sporadic bvFTD forms. When compared to AD, GRN patients present a higher impairment in frontal (P = 0.001, ŋ 2 = 0.211) and parietal (P = 0.041, ŋ 2 = 0.129) measures and a better performance in memory tasks (P = 0.020, ŋ 2 = 0.120). Sporadic-bvFTD forms are worse than AD in frontal measures (P = 0.032, ŋ 2 = 0.200), being better in both memory (P = 0.010, ŋ 2 = 0.131) and visuospatial skills (P = 0.023, ŋ 2 = 0.231). Considering these results, we conclude that GRN-bvFTD patients present a NP profile that associates the typical patterns of FTD and AD deficits. This is particularly expressive in visuoconstructive abilities, which was the more discriminative feature between groups, followed by episodic verbal memory. This study was approved by the Institutional Ethics Committee of Centro Hospitalar e Universitário de Coimbra, Portugal (CE-029/2019) on June 24, 2019., Competing Interests: None

An emergent research area in software engineering and software reliability is the use of wearable biosensors to monitor the cognitive state of software developers during software development tasks. The goal is to gather physiologic manifestations that can be linked to error-prone scenarios related to programmers' cognitive states. In this paper we investigate whether electroencephalography (EEG) can be applied to accurately identify programmers' cognitive load associated with the comprehension of code with different complexity levels. Therefore, a controlled experiment involving 26 programmers was carried. We found that features related to Theta, Alpha, and Beta brain waves have the highest discriminative power, allowing the identification of code lines and demanding higher mental effort. The EEG results reveal evidence of mental effort saturation as code complexity increases. Conversely, the classic software complexity metrics do not accurately represent the mental effort involved in code comprehension. Finally, EEG is proposed as a reference, in particular, the combination of EEG with eye tracking information allows for an accurate identification of code lines that correspond to peaks of cognitive load, providing a reference to help in the future evaluation of the space and time accuracy of programmers' cognitive state monitored using wearable devices compatible with software development activities.

Fabry disease (FD) is an X-linked hereditary disease. It results from mutations in the GLA gene, leading to deficient activity of the enzyme alpha-galactosidase A (α-Gal A) and progressive accumulation of undegraded glycosphingolipids in cell lysosomes. Enzyme replacement therapy (ERT) can improve the natural course of this disease, but an early diagnosis is crucial for a successful treatment. We describe the case of a female diagnosed with chronic proteinuric kidney disease in the postpartum period. Despite receiving optimal medical treatment, the disease progressed and she started renal replacement therapy (RRT) with peritoneal dialysis (PD). Five years later, she was enrolled in a pilot screening study for FD, and the heterozygous mutation c.870G>C (p.Met290Ile; M290I) in exon six of the GLA gene was found. The family screening revealed the presence of this mutation in the patient's father and daughter. The proband did not meet the criteria for a definitive FD diagnosis, but she remained under follow-up at our nephrology metabolic diseases consultation, as the mutation was described as pathogenic and associated with a classic FD phenotype. Later that same year, reassessment exams revealed a worsening left ventricle mass index (LVMi), a new ischemic cerebral lesion, and a substantial increase in serum globotriaosylsphingosine (LysoGb3) levels. These clinical changes led to a decision to initiate ERT. p.M290I is a previously known but poorly described GLA mutation. To our knowledge, this is the first report of p.M290I mutation-associated disease activity that offers strong evidence of its pathogenicity., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Silva et al.)

Fabry disease (FD) is an X-linked, systemic lysosomal deposition disease caused by alpha-galactosidase A (AGAL) enzyme deficiency deriving out of changes on the GLA gene. Though several mutations have been described, one must consider that even a specific mutation may present with variable clinical expression within the same family. Typically described as a disease that affects hemizygous men with no residual AGAL activity, we describe a novel FD mutation (first case of GLA T194A variant worldwide) in a 49-year-old woman presenting with a classic phenotype of FD. The patient investigation highlighted a previously not described mutation in exon 4 of the GLA gene, as for the substitution of threonine for alanine. The same mutation was identified in her children, one of them presenting with end-stage kidney disease (ESKD) in early adulthood., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Membranous nephropathy is the most common cause of nephrotic syndrome in adults. A non-negligible number of cases are associated with systemic conditions. We report a case of a 50-year-old man who presented with nephrotic syndrome six months after being diagnosed with celiac disease. Although the patient showed disappearance of circulating immunoglobulin A (IgA) anti-tissue transglutaminase antibodies following a gluten-free diet, he had a sudden onset of nephrotic syndrome presenting with severe hypoalbuminemia. Other secondary causes were promptly excluded leading to the assumption of celiac disease-associated membranous nephropathy with remission after treatment with angiotensin system blockade and a gluten-free diet. The goal of this case report is to alert the clinic towards this rare association aiming for an early diagnosis and adequate selection of long-term therapy., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Pestana et al.)