Publications by authors named "Joao Durães"

19 Publications

  • Page 1 of 1

Adult-Onset Krabbe Disease: The Importance of a Systematic Approach to Brain MRI Findings.

Neurol Clin Pract 2021 Feb;11(1):e15-e17

Department of Neurology (JD, MCM), Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal; and Unit of Rare Neurodegenerative and Neurometabolic Diseases (ES), Fondazione IRCCS Istituto Neurologico "C. Besta", Milano, Italy.

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http://dx.doi.org/10.1212/CPJ.0000000000000780DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8101315PMC
February 2021

Can EEG Be Adopted as a Neuroscience Reference for Assessing Software Programmers' Cognitive Load?

Sensors (Basel) 2021 Mar 27;21(7). Epub 2021 Mar 27.

Department of Informatics Engineering, CISUC-Centre for Informatics and Systems of the University of Coimbra, University of Coimbra, P-3030-790 Coimbra, Portugal.

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.
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http://dx.doi.org/10.3390/s21072338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8037053PMC
March 2021

Neuropsychological features of progranulin-associated frontotemporal dementia: a nested case-control study.

Neural Regen Res 2021 May;16(5):910-915

Neurology Department, Centro Hospitalar e Universitário de Coimbra; University of Coimbra, Faculty of Medicine; University of Coimbra, Center for Neuroscience and Cell Biology, Coimbra, Portugal.

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) 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 = 0.110) and visuoconstructive abilities (P = 0.039, ŋ = 0.190) than sporadic bvFTD forms. When compared to AD, GRN patients present a higher impairment in frontal (P = 0.001, ŋ = 0.211) and parietal (P = 0.041, ŋ = 0.129) measures and a better performance in memory tasks (P = 0.020, ŋ = 0.120). Sporadic-bvFTD forms are worse than AD in frontal measures (P = 0.032, ŋ = 0.200), being better in both memory (P = 0.010, ŋ = 0.131) and visuospatial skills (P = 0.023, ŋ = 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.
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http://dx.doi.org/10.4103/1673-5374.297082DOI Listing
May 2021

C-reactive protein as a predictor of mild cognitive impairment conversion into Alzheimer's disease dementia.

Exp Gerontol 2020 09 16;138:111004. Epub 2020 Jun 16.

Neurology Department, Centro Hospitalar e Universitário de Coimbra, Praceta Prof. Mota Pinto, 3000-075 Coimbra, Portugal; Faculty of Medicine, University of Coimbra, R. Larga, 3004-504 Coimbra, Portugal; Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal.

Background And Aims: Increasing evidence suggests that inflammation plays an important role in brain aging and neurodegeneration. Pathological studies demonstrate the presence of C-reactive protein (CRP) in the senile plaques and neurofibrillary tangles in Alzheimer's disease (AD) brain tissue suggesting that CRP may play a role in its neuropathological processes. Some findings suggest that midlife elevations of serum CRP are a risk factor for AD. However, others found lower CRP levels in mild or moderate AD than in controls, suggesting that CRP levels could be different in different stages of disease. We aimed to assess the role of CRP as a predictor of Mild cognitive impairment (MCI) conversion into AD dementia.

Methods: We retrospectively reviewed the cohort of MCI patients followed at the Dementia Clinic, Neurology Department of University Hospital of Coimbra. We collected demographical, neuropsychological, genetic and laboratorial variables (including serum CRP measurements at the time of baseline laboratory tests). A Cox regression model was performed adjusted for the collected variables preconsidered to be predictors of dementia and the variable being studied (CRP) to assess for independent predictors of conversion.

Results: We included 130 patients, 58.5% female, with a mean age of onset of 65.5 ± 9.1 years and age at first assessment of 69.3 ± 8.5 years. The mean CRP was 0.33 ± 0.58 mg/dl. At follow-up (mean, 36.9 ± 27.0 months) 42.3% of MCI patients converted to dementia. Lower CSF Aβ42 (HR = 0.999, 95%CI = [0.997, 1.000], p = 0.015), lower MMSE score (HR = 0.864, 95%CI = [0.510, 1.595], p = 0.008) and lower CRP quartile (HR = 0.597, 95%CI = [0.435, 0.819], p = 0.001) were independent predictors of conversion.

Conclusion: CRP may add information of risk of conversion in MCI patients. Patients with lower CRP levels appear to have a more rapid conversion to AD dementia.
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http://dx.doi.org/10.1016/j.exger.2020.111004DOI Listing
September 2020

Two sisters with myoclonus and ataxia.

Pract Neurol 2020 05 11;20(3):249-252. Epub 2020 Mar 11.

Neurology, Centro Hospitalar e Universitário de Coimbra EPE, Coimbra, Portugal.

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http://dx.doi.org/10.1136/practneurol-2019-002446DOI Listing
May 2020

Lower CSF Amyloid-Beta Predicts a Higher Mortality Rate in Frontotemporal Dementia.

Diagnostics (Basel) 2019 Oct 25;9(4). Epub 2019 Oct 25.

Neurology Department, Centro Hospitalar e Universitário de Coimbra, 3000-045 Coimbra, Portugal.

Frontotemporal lobar degeneration, the neuropathological substrate of frontotemporal dementia (FTD), is characterized by the deposition of protein aggregates, including tau. Evidence has shown concomitant amyloid pathology in some of these patients, which seems to contribute to a more aggressive disease. Our aim was to evaluate cerebrospinal fluid (CSF) amyloid-beta as a predictor of the mortality of FTD patients. We included 99 patients diagnosed with FTD-both behavioral and language variants-with no associated motor neuron disease, from whom a CSF sample was collected. These patients were followed prospectively in our center, and demographic and clinical data were obtained. The survival analysis was carried through a Cox regression model. Patients who died during follow up had a significantly lower CSF amyloid-beta than those who did not. The survival analysis demonstrated that an increased death rate was associated with a lower CSF amyloid-beta (HR = 0.999, 95% CI = [0.997, 1.000], = 0.049). Neither demographic nor clinical variables, nor CSF total tau or p-tau were significantly associated with this endpoint. These results suggest that amyloid deposition in FTD patients may be associated with a higher mortality.
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http://dx.doi.org/10.3390/diagnostics9040162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6963225PMC
October 2019

Increased CSF tau is associated with a higher risk of seizures in patients with Alzheimer's disease.

Epilepsy Behav 2019 09 2;98(Pt A):207-209. Epub 2019 Aug 2.

Neurology Department, Centro Hospitalário e Universitário de Coimbra, Praceta Prof. Mota Pinto, 3000-075 Coimbra, Portugal; Faculty of Medicine, University of Coimbra, R. Larga, 3004-504 Coimbra, Portugal; Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal.

Introduction: Neurofibrillary tangles and tau protein, the neuropathological hallmarks of Alzheimer's disease (AD), have been identified in patients with epilepsy. Tau protein was also associated with the modulation of neuronal excitability in animal models of AD.

Materials And Methods: We evaluated in 292 patients with AD the association between the risk of seizure development and AD cerebrospinal fluid (CSF) biomarkers, demographic characteristics, baseline Mini-Mental State Examination (MMSE) score, comorbidities, and apolipoprotein E status.

Results: The development of seizures was associated with younger age at dementia's onset, lower baseline MMSE, and higher CSF total tau protein levels, but only MMSE (hazard ratio [HR] = 0.935; 95% confidence interval [CI] = [0.903, 0.968]; p < 0.001) and CSF tau (HR = 1.001; 95%CI = [1.001, 1.002]; p = 0.001) were independent predictors on multivariate analysis.

Discussion: While CSF tau and lower baseline MMSE association with seizure development could in part be explained by a greater degree of cortical damage, the role of tau in the modulation of neuronal excitability may also play a role and should be further investigated.
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http://dx.doi.org/10.1016/j.yebeh.2019.06.033DOI Listing
September 2019

Woodhouse-Sakati Syndrome: First report of a Portuguese case.

Am J Med Genet A 2019 11 26;179(11):2237-2240. Epub 2019 Jul 26.

Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.

Woodhouse-Sakati Syndrome is a very rare autosomal recessive disorder caused by pathogenic variants in the DCAF17 gene, which encodes DDB1- and CUL4-associated factor 17. It is a multisystemic disorder characterized by hypogonadism, adolescent- to young adult-onset diabetes mellitus, hypothyroidism, and alopecia. Neurologic involvement includes childhood-onset moderate bilateral sensorineural hearing loss, mild intellectual disability adolescent- to young adult-onset of extrapyramidal findings, dysarthria, and dysphagia. Brain imaging typically reveals iron deposition in the globus pallidus and periventricular leukodystrophy. We report the case of a 31-year-old Portuguese female, the only child of a consanguineous couple. She presented with cognitive impairment, spastic paraparesis, lower limb dystonia, dysarthria, and dysphagia. She also had hypergonadotrophic hypogonadism associated with primary amenorrhea, insulin-dependent diabetes mellitus with retinopathy, primary hypothyroidism, moderate bilateral sensorineural hearing loss, and alopecia. Serial brain magnetic resonance imaging showed a progressive periventricular leukodystrophy with pontine involvement and significant bilateral iron deposition in the globus pallidus, substantia nigra, and red nucleus. The diagnosis of Woodhouse-Sakati Syndrome was eventually proposed and DCAF17 gene sequencing identified a novel likely pathogenic homozygous variant NG_013038.1(NM_025000.3):c.1091+2T>C. Genetic testing allowed a more accurate prognosis and a precise genetic counseling for our patient's family.
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http://dx.doi.org/10.1002/ajmg.a.61303DOI Listing
November 2019

Brain MRI features and scoring of leukodystrophy in adult-onset Krabbe disease.

Neurology 2019 08 23;93(7):e647-e652. Epub 2019 Jul 23.

From the Department of Neurology, Reference Center for Lysosomal Diseases, UF Neuro-Genetics and Metabolism (L.C., R.D., Y.N.), and Department of Neuroradiology (B.L.-Y., N.P., D.L.), Pitié-Salpêtrière Hospital, Paris; Service de Biochimie et Biologie Moléculaire Grand Est (R.F., M.P.), Unité Médicale Pathologies Métaboliques, Erythrocytaires et Dépistage Périnatal, Centre de Biologie et de Pathologie Est, Hospices Civils de Lyon, Bron; UMR 5305 CNRS/UCBL (R.F.), Lyon, France; Department of Medicine, Surgery and Neurosciences (A.F., S.S.), Unit of Neurology and Neurometabolic Diseases, Medical School, University of Siena; Neuroradiology Unit (A.C.), Azienda Ospedaliera Universitaria Senese, Siena, Italy; Department of Neurology (M.C.M., J.D.), Coimbra Hospital and University Centre, Portugal; Department of Neurology (S.H.K.), College of Medicine, Hanyang University, Seoul, Korea; Division of Neurology (H.A.), Hyogo Prefectural Amagasaki General Medical Center, Hyogo, Japan; Department of Neurology (B.A.), La Timone Hospital; Aix-Marseille University (B.A.), CNRS, CRMBM UMR, Marseille; Department of Neurology (X.A.), Montpellier University Hospital, France; Department of Neurology (Y.D.), Xuan Wu Hospital, Capital Medical University, Beijing, China; Department of Neurology (R.H.), Royal Brisbane Hospital, Brisbane, Australia; Laboratory of Neurogenetics of Motion and Department of Neuroradiology (R.L.P.), Montréal Neurological Institute and Hospital, McGill University, Montréal; Department of Radiology (C.L.), Department of Pathology and Laboratory Medicine (C.L.), International Collaboration on Repair Discoveries (ICORD) (C.L.), Department of Physics and Astronomy (C.L.), and Division of Endocrinology, Department of Medicine (S.M.S.), University of British Columbia, Vancouver, Canada; Department of Neurology (K.N.), Division of Clinical Medicine, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan; Department of Radiology (R.R.), Uppsala University, Sweden; Department of Neurology and Hertie-Institute for Clinical Brain Research (L.S.), Eberhard-Karls-University; German Center of Neurodegenerative Diseases (DZNE) (L.S.), Tübingen, Germany; Department of Neurology (F.V.), Caen-Normandie University Hospital, Caen; Inserm U1077 (F.V.), EPHE, Caen-Normandie University, Caen, France; and Department of Neurology and Stroke (K.J.), Medical University of Lodz, Poland.

Objective: To perform a systematic analysis and scoring of brain MRI white matter hyperintensities (WMH) in adult-onset Krabbe disease.

Methods: We retrospectively collected basic clinical data and the first available brain MRI from patients with confirmed Krabbe disease with first clinical manifestations beyond 10 years of age. Data were obtained from our reference center for lysosomal diseases (n = 6) and from contacted authors of published articles describing patients with adult-onset Krabbe disease (n = 15). T2-weighted fluid-attenuated inversion recovery images of each patient were analyzed and scored using a radiologic score of WMH in a single center.

Results: The corticospinal tract was always affected by WMH (100% of patients), however, with some distinctions along the tract: the precentral gyrus (100%), corona radiata (95%), and posterior internal capsule (81%) were highly abnormal, whereas the mesencephalon (57%), pons (52%), and medulla oblongata (5%) were less affected. WMH were also frequently present in the posterior lateral periventricular white matter (95%), optic radiations (86%), postcentral gyrus (71%), medial lemniscus (62%), and corpus callosum, especially in the isthmus (71%), whereas the genu was always normal. A few patients did not have the classical MRI pattern but extensive hyperintensities (n = 3), or patchy distribution of hyperintensities mimicking an acquired etiology (n = 2), or very subtle hyperintensities of the corticospinal tract (n = 1).

Conclusions: We specified the main locations of WMH, which were observed in the earliest stages of the disease and were also present in patients with atypical MRI pattern, highlighting the importance of radiologic features to guide the diagnosis.
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http://dx.doi.org/10.1212/WNL.0000000000007943DOI Listing
August 2019

Ischaemic stroke as the initial manifestation of systemic amyloidosis.

BMJ Case Rep 2019 Jun 29;12(6). Epub 2019 Jun 29.

Neurology, Centro Hospitalar e Universitario de Coimbra EPE, Coimbra, Portugal.

A previously healthy 54-year-old woman was admitted to the stroke unit with an acute ischaemic stroke attributed to atrial fibrillation newly diagnosed at the emergency room. Nevertheless, preliminary investigation on stroke aetiology revealed incidental hypoalbuminaemia in the context of nephrotic syndrome, while clinically, the patient developed progressive signs of cardiac failure raising the suspicion of an underlying disorder. Systemic amyloidosis was histologically confirmed a few weeks after hospital admission. The rare presentation and non-specific symptom constellation contributed to delayed institution of the appropriated treatment regimen at a point where multiorganic involvement was irreversible leading to death only 2 months after the first manifestation. The presented case reminds us of the importance of always keeping in mind this rarer cause of ischaemic stroke since an early diagnosis remains the key to a more hopeful prognosis.
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http://dx.doi.org/10.1136/bcr-2018-228979DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6605910PMC
June 2019

Hypocomplementemic urticarial vasculitis and multiple Sclerosis: A rare association or an atypical presentation?

Mult Scler Relat Disord 2019 May 15;30:244-246. Epub 2019 Feb 15.

Neurology Department, Centro Hospitalar e Universitário de Coimbra, Coimbra 3000-075, Portugal.

Background: Multiple Sclerosis (MS) has been associated with several immune-mediated diseases but the mechanisms that explain such associations, as well as their implications in clinical practice and treatment are rarely discussed.

Case Presentation: We report the case of a patient with a history of MS since she was 27 years old, followed by a diagnosis of Hypocomplementemic Urticarial Vasculitis (HUV) seven years later. Several disease-modifying treatments for MS and HUV were used but with limited benefit in both diseases and significant MS progression. Activity of both diseases was later stabilized with Rituximab. We discuss the hypotheses of a central nervous system involvement in urticarial vasculitis or an association between MS and HUV, and examine the challenges in their management.

Conclusions: In the presence of concurrent immune-mediated diseases, the diagnosis of MS can be challenging. This clinical presentation posed significant difficulties in disease management, influencing therapeutic options and their effectiveness/adverse effects profile. The best approach in MS patients with concurrent autoimmune diseases remains to be established and more reports are needed to help clarify this subject.
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http://dx.doi.org/10.1016/j.msard.2019.02.020DOI Listing
May 2019

Increased risk of melanoma in C9ORF72 repeat expansion carriers: A case-control study.

Muscle Nerve 2019 03 27;59(3):362-365. Epub 2018 Dec 27.

CHUC, Serviço de Neurologia, Praceta Prof. Mota Pinto, 3000-075, Coimbra, Portugal.

Introduction: Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are considered part of the same pathological spectrum. There is an increased risk of ALS in patients who have had melanoma. The risk of FTLD in melanoma (or cancer) patients is unknown. We aimed to study if C9ORF72 expansion is linked to a higher prevalence of melanoma.

Methods: We selected patients with a diagnosis in the ALS-FTLD spectrum who were tested for pathogenic mutations. Medical history was reviewed, to identify those with pathologically documented melanomas.

Results: We included 189 patients. Sixty-two had identified pathogenic mutations (39 C9ORF72). C9ORF72 carriers had a significantly higher risk of melanoma (odds ratio = 24.709; P < 0.007). There was no association with phenotype.

Conclusions: These findings suggest that patients with a history of melanoma may have an increased probability of carrying a C9ORF72 repeat expansion. ALS or FTLD carriers of C9ORF72 should undergo surveillance for skin changes. Muscle Nerve 59:362-365, 2019.
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http://dx.doi.org/10.1002/mus.26383DOI Listing
March 2019

Demyelinating disease of the central nervous system associated with Pembrolizumab treatment for metastatic melanoma.

Mult Scler 2019 06 12;25(7):1005-1008. Epub 2018 Oct 12.

Neurology Department, Coimbra Hospital and Universitary Centre, Coimbra, Portugal.

Immune checkpoint inhibitors are used in metastatic melanoma with good efficacy and safety profile. We report the first case of an inflammatory demyelinating disease of the central nervous system during treatment with Pembrolizumab and discuss the evidence in the literature supporting its causative role. The patient had a good clinical recovery after intravenous steroids, plasma exchange and discontinuation of Pembrolizumab. Due to the expected increase in the importance of immune checkpoint inhibitors in cancer treatment, it is important to be aware of neurological adverse events, as early treatment usually leads to good clinical responses.
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http://dx.doi.org/10.1177/1352458518803724DOI Listing
June 2019

The Head Turning Sign in Dementia and Mild Cognitive Impairment: Its Relationship to Cognition, Behavior, and Cerebrospinal Fluid Biomarkers.

Dement Geriatr Cogn Disord 2018 9;46(1-2):42-49. Epub 2018 Aug 9.

Neurology Department, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.

Background/aims: The head turning sign (HTS) is frequently noticed in clinical practice, but few studies have investigated its etiological and neuropsychological correlates.

Methods: The presence and frequency of the HTS was operationalized and prospectively evaluated in patients with Alzheimer's disease (AD), amnestic mild cognitive impairment (MCI), and behavioral-variant frontotemporal dementia (bvFTD). Cerebrospinal fluid (CSF) samples for AD biomarkers were collected. Mini-Mental State Examination, Montreal Cognitive Assessment, Geriatric Depression Scale (GDS), and insight scale scores were ascertained.

Results: A total of 84 patients were included. The HTS was more prevalent in AD than in MCI or bvFTD. It correlated negatively with cognitive measures and depression. It also had a positive correlation with CSF total tau and hyperphosphorylated tau proteins. Total tau protein and GDS score were the only variables independently associated with the HTS.

Conclusions: The presence of the HTS in a cognitively impaired individual suggests a diagnosis of AD. A higher HTS frequency correlates with higher CSF total tau levels, a smaller GDS score, and worse cognitive measures. In the MCI subgroup, the HTS may suggest a higher risk of progression.
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http://dx.doi.org/10.1159/000486531DOI Listing
November 2018

The role of the insula in intuitive expert bug detection in computer code: an fMRI study.

Brain Imaging Behav 2019 Jun;13(3):623-637

ICNAS/CIBIT, Coimbra Institute for Biomedical Imaging and Life Sciences, University of Coimbra, Azinhaga de Santa Comba, 3000-548, Coimbra, Portugal.

Software programming is a complex and relatively recent human activity, involving the integration of mathematical, recursive thinking and language processing. The neural correlates of this recent human activity are still poorly understood. Error monitoring during this type of task, requiring the integration of language, logical symbol manipulation and other mathematical skills, is particularly challenging. We therefore aimed to investigate the neural correlates of decision-making during source code understanding and mental manipulation in professional participants with high expertise. The present fMRI study directly addressed error monitoring during source code comprehension, expert bug detection and decision-making. We used C code, which triggers the same sort of processing irrespective of the native language of the programmer. We discovered a distinct role for the insula in bug monitoring and detection and a novel connectivity pattern that goes beyond the expected activation pattern evoked by source code understanding in semantic language and mathematical processing regions. Importantly, insula activity levels were critically related to the quality of error detection, involving intuition, as signalled by reported initial bug suspicion, prior to final decision and bug detection. Activity in this salience network (SN) region evoked by bug suspicion was predictive of bug detection precision, suggesting that it encodes the quality of the behavioral evidence. Connectivity analysis provided evidence for top-down circuit "reutilization" stemming from anterior cingulate cortex (BA32), a core region in the SN that evolved for complex error monitoring such as required for this type of recent human activity. Cingulate (BA32) and anterolateral (BA10) frontal regions causally modulated decision processes in the insula, which in turn was related to activity of math processing regions in early parietal cortex. In other words, earlier brain regions used during evolution for other functions seem to be reutilized in a top-down manner for a new complex function, in an analogous manner as described for other cultural creations such as reading and literacy.
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http://dx.doi.org/10.1007/s11682-018-9885-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6538820PMC
June 2019

Disclosing the functional changes of two genetic alterations in a patient with Chronic Progressive External Ophthalmoplegia: Report of the novel mtDNA m.7486G>A variant.

Neuromuscul Disord 2018 04 23;28(4):350-360. Epub 2017 Nov 23.

FMUC - Faculty of Medicine, University of Coimbra, Coimbra, Portugal; CNC - Center for Neuroscience and Cell Biology, Laboratory of Biochemical Genetics, University of Coimbra, Coimbra, Portugal. Electronic address:

Chronic Progressive External Ophthalmoplegia (CPEO) is characterized by ptosis and ophthalmoplegia and is usually caused by mitochondrial DNA (mtDNA) deletions or mt-tRNA mutations. The aim of the present work was to clarify the genetic defect in a patient presenting with CPEO and elucidate the underlying pathogenic mechanism. This 62-year-old female first developed ptosis of the right eye at the age of 12 and subsequently the left eye at 45 years, and was found to have external ophthalmoplegia at the age of 55 years. Histopathological abnormalities were detected in the patient's muscle, including ragged-red fibres, a mosaic pattern of COX-deficient muscle fibres and combined deficiency of respiratory chain complexes I and IV. Genetic investigation revealed the "common deletion" in the patient's muscle and fibroblasts. Moreover, a novel, heteroplasmic mt-tRNA variant (m.7486G>A) in the anticodon loop was detected in muscle homogenate (50%), fibroblasts (11%) and blood (4%). Single-fibre analysis showed segregation with COX-deficient fibres for both genetic alterations. Assembly defects of mtDNA-encoded complexes were demonstrated in fibroblasts. Functional analyses showed significant bioenergetic dysfunction, reduction in respiration rate and ATP production and mitochondrial depolarization. Multilamellar bodies were detected by electron microscopy, suggesting disturbance in autophagy. In conclusion, we report a CPEO patient with two possible genetic origins, both segregating with biochemical and histochemical defect. The "common mtDNA deletion" is the most likely cause, yet the potential pathogenic effect of a novel mt-tRNA variant cannot be fully excluded.
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http://dx.doi.org/10.1016/j.nmd.2017.11.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5952895PMC
April 2018

Association between butyrylcholinesterase and cerebrospinal fluid biomarkers in Alzheimer's disease patients.

Neurosci Lett 2017 02 17;641:101-106. Epub 2017 Jan 17.

Laboratory of Neurochemistry, Coimbra University Hospital, Coimbra, Portugal; Faculty of Medicine, University of Coimbra, Coimbra, Portugal.

The deficit of cholinergic activity is one of the main findings in Alzheimer's disease (AD), and is related to the synthesis of acetylcholine, and the hydrolysing enzymes, acetylcholinesterase and butyrylcholinesterase (BuChE). Together with the Apolipoprotein E-ε4 allele (ApoE-ε4), the BuChE-K variant has been proposed to increase AD risk in certain populations. In addition, this polymorphism has been associated with a lower capacity to attenuate β-amyloid aggregation. In the present study we explored the interaction of the BuChE-K variant with its activity in CSF, conventional AD biomarkers and ApoE genotype. 217 AD patients and 200 age-matched controls were genotyped for the ApoE and the BuChE-K variant. BuChE activity in CSF, as well as the levels of the CSF-AD biomarkers amyloid-beta 42 (Aβ42), total and hyperphosphorylated tau (t-tau and p-tau) were determined in 88 of these patients. The results showed no significant differences in the BuChE-K variant distribution between patients and controls. No influence of the BuChE-K variant was seen neither in CSF BuChE activity, nor in the levels of Aβ42, t-tau and p-tau in AD patients. ApoE genotype also did not seem to influence CSF BuChE activity. Interestingly, in AD patients, an association between high CSF BuChE activity and increased levels of CSF Aβ42 was shown, particularly in ApoE-ε4 allele carriers. In our population, the BuChE-K variant does not seem to confer risk for AD or to influence the activity of the enzyme in CSF. However, we demonstrated an association between BuChE activity, ApoE-ε4 genotype and CSF Aβ42 levels, highlighting the importance of assessing BuChE activity as a possible modulator of Aβ load in the brain.
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http://dx.doi.org/10.1016/j.neulet.2017.01.036DOI Listing
February 2017

Adolescent-onset Krabbe disease with an initial diagnosis of multiple sclerosis and a novel mutation.

BMJ Case Rep 2015 Sep 22;2015. Epub 2015 Sep 22.

Neurology Department, Coimbra Hospital and University Centre, Coimbra, Portugal.

Krabbe disease is a rare autosomal recessive leucodystrophy, with <5% of the cases having an adolescent-onset form. A 30-year-old woman with a history of a subacute episode of gait impairment at 14 years of age, and mild spastic paraparesis since then, was followed with an initial diagnosis of multiple sclerosis. After 10 years of slow disease progression without response to treatment, the initial diagnosis was reviewed, and an extensive metabolic work up revealed decreased activity of galactocerebrosidase. Genetic testing of the GALC gene proved the diagnosis of Krabbe disease and found a novel mutation. This case highlights the value of a critical eye in the initial differential diagnosis, mainly in the presence of atypical findings.
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http://dx.doi.org/10.1136/bcr-2015-210625DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4593283PMC
September 2015