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1. Plasma Neurofilament Light Chain: A Potential Biomarker for Neurological Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

Author

Azcue, Naiara, Tijero-Merino, Beatriz, Acera, Marian, Pérez-Garay, Raquel, Fernández-Valle, Tamara, Ayo-Mentxakatorre, Naia, Ruiz-López, Marta, Lafuente, Jose Vicente, Gómez Esteban, Juan Carlos, and Del Pino, Rocio

Subjects
CHRONIC fatigue syndrome, AUTONOMIC nervous system, COGNITIVE testing, VISUAL memory, NEUROPSYCHOLOGICAL tests
Abstract

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex disorder characterized by heterogeneous symptoms, which lack specific biomarkers for its diagnosis. This study aimed to investigate plasma neurofilament light chain (NfL) levels as a potential biomarker for ME/CFS and explore associations with cognitive, autonomic, and neuropathic symptoms. Here, 67 ME/CFS patients and 43 healthy controls (HCs) underwent comprehensive assessments, including neuropsychological evaluation, autonomic nervous system (ANS) testing, and plasma NfL level analysis. ME/CFS patients exhibited significantly higher plasma NfL levels compared to HC (F = 4.30, p < 0.05). Correlations were observed between NfL levels and cognitive impairment, particularly in visuospatial perception (r = −0.42; p ≤ 0.001), verbal memory (r = −0.35, p ≤ 0.005), and visual memory (r = −0.26; p < 0.05) in ME/CFS. Additionally, higher NfL levels were associated with worsened autonomic dysfunction in these patients, specifically in parasympathetic function (F = 9.48, p ≤ 0.003). In ME/CFS patients, NfL levels explained up to 17.2% of the results in cognitive tests. Unlike ME/CFS, in HC, NfL levels did not predict cognitive performance. Elevated plasma NfL levels in ME/CFS patients reflect neuroaxonal damage, contributing to cognitive dysfunction and autonomic impairment. These findings support the potential role of NfL as a biomarker for neurological dysfunction in ME/CFS. Further research is warranted to elucidate underlying mechanisms and clinical implications. [ABSTRACT FROM AUTHOR]

Published
2024
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2. Impact of the <scp>COVID</scp> ‐19 pandemic on clinical autonomic practice in Europe: a survey of the European Academy of Neurology and the European Federation of Autonomic Societies

Author

Fanciulli, Alessandra, Leys, Fabian, Krbot Skorić, Magdalena, Reis Carneiro, Diogo, Calandra‐Buonaura, Giovanna, Camaradou, Jennifer, Chiaro, Giacomo, Cortelli, Pietro, Falup‐ Pecurariu, Cristian, Granata, Roberta, Guaraldi, Pietro, Helbok, Raimund, Hilz, Max J., Iodice, Valeria, Jordan, Jens, Kaal, Evert C. A., Kamondi, Anita, Pavy Le Traon, Anne, Rocha, Isabel, Sellner, Johann, Senard, Jean Michel, Terkelsen, Astrid, Wenning, Gregor K., Moro, Elena, Berger, Thomas, Thijs, Roland D., Struhal, Walter, Habek, Mario, Adamec, Ivan, Aerts, Arnaud, Campese, Nicole, Canta, Leo L. R., Delamont, Robert Shane, de Lange, Frederik, Del Sorbo, Francesca, Devigili, Grazia, Di Leo, Rita, Dinh, Trang, Fortrat, Jacques‐Olivier, Gierthmühlen, Janne, Hemels, Martin, Köhn, Julia, Krøigård, Thomas, Lipp, Axel, Maier, Andrea, Marinelli, Lucio, Mazzeo, Anna, Milenkovic, Ivan, Motyl, Maciej, Sora, Maria Grazia Natali, Navarro‐Otano, Judith, Nilsen, Kristian Bernhard, Oliveira, Mario, Omland, Petter Moe, Pelliccioni, Giuseppe, Pereon, Yann, Resch, Roland Josef, Rocchi, Camilla, Roche, Frederic, Rutten, Joost, Tijero‐Merino, Beatriz, Tutaj, Marcin, van der Heijden‐Montfroy, A. M. H. G., van Hoeve, Bas J. A., van Orshoven, Narender, Wang, Ruihao, Graggen, Werner J. Z’., and the Collaborators of European Network of Neurological ANS laboratories

Subjects
orthostatic hypotension, COVID-19 infection, vaccination, POTS, autonomic nervous system, postural orthostatic tachycardia syndrome, syncope, telemedicineCOVID-19 infection, COVID-19 vaccination, Neurology, telemedicine, Neurology (clinical)
Abstract

Background and purpose: The objective was to investigate the impact of the coronavirus disease 2019 (COVID-19) pandemic on European clinical autonomic practice. Methods: Eighty-four neurology-driven or interdisciplinary autonomic centers in 22 European countries were invited to fill in a web-based survey between September and November 2021. Results: Forty-six centers completed the survey (55%). During the first pandemic year, the number of performed tilt-table tests, autonomic outpatient and inpatient visits decreased respectively by 50%, 45% and 53%, and every third center reported major adverse events due to postponed examinations or visits. The most frequent newly diagnosed or worsened cardiovascular autonomic disorders after COVID-19 infection included postural orthostatic tachycardia syndrome, orthostatic hypotension and recurrent vasovagal syncope, deemed to be likely related to the infection by ≥50% of the responders. Forty-seven percent of the responders also reported about people with new onset of orthostatic intolerance but negative tilt-table findings, and 16% about people with psychogenic pseudosyncope after COVID-19. Most patients were treated non-pharmacologically and symptomatic recovery at follow-up was observed in ≥45% of cases. By contrast, low frequencies of newly diagnosed cardiovascular autonomic disorders following COVID-19 vaccination were reported, most frequently postural orthostatic tachycardia syndrome and recurrent vasovagal syncope, and most of the responders judged a causal association unlikely. Non-pharmacological measures were the preferred treatment choice, with 50%–100% recovery rates at follow-up. Conclusions: Cardiovascular autonomic disorders may develop or worsen following a COVID-19 infection, whilst the association with COVID-19 vaccines remains controversial. Despite the severe pandemic impact on European clinical autonomic practice, a specialized diagnostic work-up was pivotal to identify non-autonomic disorders in people with post-COVID-19 orthostatic complaints.

Published
2023
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3. Dysautonomia and small fiber neuropathy in post-COVID condition and Chronic Fatigue Syndrome

Author

Azcue, Naiara, primary, Pino, Rocio Del, additional, Acera, Marian, additional, Valle, Tamara Fernandez, additional, Mentxakatorre, Naia Ayo, additional, Concha, Tomás Pérez, additional, Murueta-Goyena, Ane, additional, Lafuente, Jose Vicente, additional, Prada-Iñurrategui, Álvaro, additional, de Munain, Adolfo López, additional, Ruiz-Irastorza, Guillermo, additional, Martín-Iglesias, Daniel, additional, Ribacoba, Laureano, additional, Gabilondo, Iñigo, additional, Gómez-Esteban, Juan Carlos, additional, and Tijero-Merino, Beatriz, additional

Published
2023
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4. Diagnostic classification of Parkinson’s disease based on non-motor manifestations and machine learning strategies

Author

Arquitectura y Tecnología de Computadores, Neurociencias, Konputagailuen Arkitektura eta Teknologia, Neurozientziak, Martínez Eguiluz, Maitane, Arbelaiz Gallego, Olatz, Gurrutxaga Goikoetxea, Ibai, Muguerza Rivero, Javier Francisco, Perona Balda, Iñigo, Murueta-Goyena Larrañaga, Ane, Acera Gil, María Ángeles, Del Pino Sáez, Rocío, Tijero Merino, Beatriz, Gómez Esteban, Juan Carlos, Gabilondo Cuellar, Iñigo, Arquitectura y Tecnología de Computadores, Neurociencias, Konputagailuen Arkitektura eta Teknologia, Neurozientziak, Martínez Eguiluz, Maitane, Arbelaiz Gallego, Olatz, Gurrutxaga Goikoetxea, Ibai, Muguerza Rivero, Javier Francisco, Perona Balda, Iñigo, Murueta-Goyena Larrañaga, Ane, Acera Gil, María Ángeles, Del Pino Sáez, Rocío, Tijero Merino, Beatriz, Gómez Esteban, Juan Carlos, and Gabilondo Cuellar, Iñigo

Abstract

Non-motor manifestations of Parkinson’s disease (PD) appear early and have a significant impact on the quality of life of patients, but few studies have evaluated their predictive potential with machine learning algorithms. We evaluated 9 algorithms for discriminating PD patients from controls using a wide collection of non-motor clinical PD features from two databases: Biocruces (96 subjects) and PPMI (687 subjects). In addition, we evaluated whether the combination of both databases could improve the individual results. For each database 2 versions with different granularity were created and a feature selection process was performed. We observed that most of the algorithms were able to detect PD patients with high accuracy (>80%). Support Vector Machine and Multi-Layer Perceptron obtained the best performance, with an accuracy of 86.3% and 84.7%, respectively. Likewise, feature selection led to a significant reduction in the number of variables and to better performance. Besides, the enrichment of Biocruces database with data from PPMI moderately benefited the performance of the classification algorithms, especially the recall and to a lesser extent the accuracy, while the precision worsened slightly. The use of interpretable rules obtained by the RIPPER algorithm showed that simply using two variables (autonomic manifestations and olfactory dysfunction), it was possible to achieve an accuracy of 84.4%. Our study demonstrates that the analysis of non-motor parameters of PD through machine learning techniques can detect PD patients with high accuracy and recall, and allows us to select the most discriminative non-motor variables to create potential tools for PD screening.

Published
2023

6. Dysautonomia in COVID-19 Patients: A Narrative Review on Clinical Course, Diagnostic and Therapeutic Strategies

Author

Medicina, Medikuntza, Carmona Torre, Francisco, Mínguez Olaondo, Ane, López Bravo, Alba, Tijero Merino, Beatriz, Grozeva, Vasselina, Walcker, Michaela, Azcune Galparsoro, Arkaitz, López de Muniain, Adolfo, Alcaide, Ana Belén, Quiroga, Jorge, Del Pozo, José Luis, Gómez Esteban, Juan Carlos, Medicina, Medikuntza, Carmona Torre, Francisco, Mínguez Olaondo, Ane, López Bravo, Alba, Tijero Merino, Beatriz, Grozeva, Vasselina, Walcker, Michaela, Azcune Galparsoro, Arkaitz, López de Muniain, Adolfo, Alcaide, Ana Belén, Quiroga, Jorge, Del Pozo, José Luis, and Gómez Esteban, Juan Carlos

Abstract

IntroductionOn March 11, 2020, the World Health Organization sounded the COVID-19 pandemic alarm. While efforts in the first few months focused on reducing the mortality of infected patients, there is increasing data on the effects of long-term infection (Post-COVID-19 condition). Among the different symptoms described after acute infection, those derived from autonomic dysfunction are especially frequent and limiting. ObjectiveTo conduct a narrative review synthesizing current evidence of the signs and symptoms of dysautonomia in patients diagnosed with COVID-19, together with a compilation of available treatment guidelines. ResultsAutonomic dysfunction associated with SARS-CoV-2 infection occurs at different temporal stages. Some of the proposed pathophysiological mechanisms include direct tissue damage, immune dysregulation, hormonal disturbances, elevated cytokine levels, and persistent low-grade infection. Acute autonomic dysfunction has a direct impact on the mortality risk, given its repercussions on the respiratory, cardiovascular, and neurological systems. Iatrogenic autonomic dysfunction is a side effect caused by the drugs used and/or admission to the intensive care unit. Finally, late dysautonomia occurs in 2.5% of patients with Post-COVID-19 condition. While orthostatic hypotension and neurally-mediated syncope should be considered, postural orthostatic tachycardia syndrome (POTS) appears to be the most common autonomic phenotype among these patients. A review of diagnostic and treatment guidelines focused on each type of dysautonomic condition was done. ConclusionSymptoms deriving from autonomic dysfunction involvement are common in those affected by COVID-19. These symptoms have a great impact on the quality of life both in the short and medium to long term. A better understanding of the pathophysiological mechanisms of Post-COVID manifestations that affect the autonomic nervous system, and targeted therapeutic management could help reduce the sequela

Published
2022

7. Heart-brain synchronization breakdown in Parkinson's disease

Author

Neurociencias, Neurozientziak, Iñiguez, Martín, Jiménez Marín, Antonio, Erramuzpe Aliaga, Asier, Acera, Marian, Tijero Merino, Beatriz, Murueta-Goyena Larrañaga, Ane, Del Pino Sáez, Rocío, Fernández Valle, Tamara, Carmona Abellán, Mar, Cabrera Zubizarreta, Alberto, Gómez Esteban, Juan Carlos, Cortés Díaz, Jesús María, Gabilondo Cuellar, Iñigo, Neurociencias, Neurozientziak, Iñiguez, Martín, Jiménez Marín, Antonio, Erramuzpe Aliaga, Asier, Acera, Marian, Tijero Merino, Beatriz, Murueta-Goyena Larrañaga, Ane, Del Pino Sáez, Rocío, Fernández Valle, Tamara, Carmona Abellán, Mar, Cabrera Zubizarreta, Alberto, Gómez Esteban, Juan Carlos, Cortés Díaz, Jesús María, and Gabilondo Cuellar, Iñigo

Abstract

Heart rate variability (HRV) abnormalities are potential early biomarkers in Parkinson's disease (PD) but their relationship with central autonomic network (CAN) activity is not fully understood. We analyzed the synchronization between HRV and brain activity in 31 PD patients and 21 age-matched healthy controls using blood-oxygen-level-dependent (BOLD) signals from resting-state functional brain MRI and HRV metrics from finger plethysmography recorded for 7.40 min. We additionally quantified autonomic symptoms (SCOPA-AUT) and objective autonomic cardiovascular parameters (blood pressure and heart rate) during deep breathing, Valsalva, and head-up tilt, which were used to classify the clinical severity of dysautonomia. We evaluated HRV and BOLD signals synchronization (HRV-BOLD-sync) with Pearson lagged cross-correlations and Fisher's statistics for combining window-length-dependent HRV-BOLD-Sync Maps and assessed their association with clinical dysautonomia. HRV-BOLD-sync was lower significantly in PD than in controls in various brain regions within CAN or in networks involved in autonomic modulation. Moreover, heart-brain synchronization index (HBSI), which quantifies heart-brain synchronization at a single-subject level, showed an inverse exposure-response relationship with dysautonomia severity, finding the lowest HBSI in patients with severe dysautonomia, followed by moderate, mild, and, lastly, controls. Importantly, HBSI was associated in PD, but not in controls, with Valsalva pressure recovery time (sympathetic), deep breathing E/I ratio (cardiovagal), and SCOPA-AUT. Our findings support the existence of heart-brain de-synchronization in PD with an impact on clinically relevant autonomic outcomes.

Published
2022

8. Brain fog of post-COVID-19 condition and Chronic Fatigue Syndrome, same medical disorder?

Author

Neurociencias, Neurozientziak, Azcue González, Naiara, Gómez Esteban, Juan Carlos, Acera Gil, María Ángeles, Tijero Merino, Beatriz, Fernández Valle, Tamara, Ayo Mentxakatorre, Naia, Pérez Concha, Tomás, Murueta-Goyena Larrañaga, Ane, Lafuente Sánchez, José Vicente, Prada, Alvaro, López de Munain Arregui, Adolfo José, Ruiz Irastorza, Guillermo, Ribacoba, Laureano, Gabilondo Cuellar, Iñigo, Del Pino Sáez, Rocío, Neurociencias, Neurozientziak, Azcue González, Naiara, Gómez Esteban, Juan Carlos, Acera Gil, María Ángeles, Tijero Merino, Beatriz, Fernández Valle, Tamara, Ayo Mentxakatorre, Naia, Pérez Concha, Tomás, Murueta-Goyena Larrañaga, Ane, Lafuente Sánchez, José Vicente, Prada, Alvaro, López de Munain Arregui, Adolfo José, Ruiz Irastorza, Guillermo, Ribacoba, Laureano, Gabilondo Cuellar, Iñigo, and Del Pino Sáez, Rocío

Abstract

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is characterized by persistent physical and mental fatigue. The post-COVID-19 condition patients refer physical fatigue and cognitive impairment sequelae. Given the similarity between both conditions, could it be the same pathology with a different precipitating factor? Objective: To describe the cognitive impairment, neuropsychiatric symptoms, and general symptomatology in both groups, to find out if it is the same pathology. As well as verify if the affectation of smell is related to cognitive deterioration in patients with post-COVID-19 condition. Methods: The sample included 42 ME/CFS and 73 post-COVID-19 condition patients. Fatigue, sleep quality, anxiety and depressive symptoms, the frequency and severity of different symptoms, olfactory function and a wide range of cognitive domains were evaluated. Results: Both syndromes are characterized by excessive physical fatigue, sleep problems and myalgia. Sustained attention and processing speed were impaired in 83.3% and 52.4% of ME/CFS patients while in post-COVID-19 condition were impaired in 56.2% and 41.4% of patients, respectively. Statistically significant differences were found in sustained attention and visuospatial ability, being the ME/CFS group who presented the worst performance. Physical problems and mood issues were the main variables correlating with cognitive performance in post-COVID-19 patients, while in ME/CFS it was anxiety symptoms and physical fatigue. Conclusions: The symptomatology and cognitive patterns were similar in both groups, with greater impairment in ME/CFS. This disease is characterized by greater physical and neuropsychiatric problems compared to post-COVID-19 condition. Likewise, we also propose the relevance of prolonged hyposmia as a possible marker of cognitive deterioration in patients with post-COVID-19.

Published
2022

9. Clinical autonomic nervous system laboratories in Europe. A joint survey of the European Academy of Neurology and the European Federation of Autonomic Societies

Author

Habek, Mario, Leys, Fabian, Krbot Skorić, Magdalena, Reis Carneiro, Diogo, Calandra‐Buonaura, Giovanna, Camaradou, Jennifer, Chiaro, Giacomo, Cortelli, Pietro, Falup‐Pecurariu, Cristian, Granata, Roberta, Guaraldi, Pietro, Helbok, Raimund, Hilz, Max J., Iodice, Valeria, Jordan, Jens, Kaal, Evert C. A., Kamondi, Anita, Pavy Le Traon, Anne, Rocha, Isabel, Sellner, Johann, Senard, Jean Michel, Terkelsen, Astrid, Wenning, Gregor K., Berger, Thomas, Thijs, Roland D., Struhal, Walter, Fanciulli, Alessandra, Adamec, Ivan, Aerts, Arnaud, Canta, Leo L.R., Delamont, Robert Shane, de Lange, Frederik, Del Sorbo, Francesca, Devigili, Grazia, Di Leo, Rita, Dinh, Trang, Fortrat, Jacques‐Olivier, Gierthmühlen, Janne, Hemels, Martin, Köhn, Julia, Krøigård, Thomas, Lipp, Axel, Maier, Andrea, Marinelli, Lucio, Mazzeo, Anna, Milenkovic, Ivan, Motyl, Maciej, Natali Sora, Maria Grazia, Navarro‐Otano, Judith, Nilsen, Kristian Bernhard, Oliveira, Mario, Omland, Petter Moe, Pelliccioni, Giuseppe, Pereon, Yann, Resch, Roland Josef, Rocchi, Camilla, Roche, Frederic, Rutten, Joost, Tijero Merino, Beatriz, Tutaj, Marcin, van der Heijden‐Montfroy, A.M.H.G., van Hoeve, Bas J.A., van Orshoven, Narender, Wang, Ruihao, Z’Graggen, Werner J., Habek M., Leys F., Krbot Skoric M., Reis Carneiro D., Calandra-Buonaura G., Camaradou J., Chiaro G., Cortelli P., Falup-Pecurariu C., Granata R., Guaraldi P., Helbok R., Hilz M.J., Iodice V., Jordan J., Kaal E.C.A., Kamondi A., Pavy Le Traon A., Rocha I., Sellner J., Senard J.M., Terkelsen A., Wenning G.K., Berger T., Thijs R.D., Struhal W., Fanciulli A., Adamec I., Aerts A., Canta L.L.R., Delamont R.S., de Lange F., Del Sorbo F., Devigili G., Di Leo R., Dinh T., Fortrat J.-O., Gierthmuhlen J., Hemels M., Kohn J., Kroigard T., Lipp A., Maier A., Marinelli L., Mazzeo A., Milenkovic I., Motyl M., Natali Sora M.G., Navarro-Otano J., Nilsen K.B., Oliveira M., Omland P.M., Pelliccioni G., Pereon Y., Resch R.J., Rocchi C., Roche F., Rutten J., Tijero Merino B., Tutaj M., van der Heijden-Montfroy A.M.H.G., van Hoeve B.J.A., van Orshoven N., Wang R., Z'Graggen W.J., Cardiology, ACS - Heart failure & arrhythmias, and Repositório da Universidade de Lisboa

Subjects
sweat test, sweat tests, neurological disorders, Autonomic Nervous System, Autonomic Nervous System Disease, (disorders of) autonomic nervous system, cardiovascular autonomic function test, Composite Autonomic Severity Score, orthostatic hypotension, Neurology, syncope, Consciousness, disorders, neurodisparity, Autonomic nervous system, disorders, Surveys and Questionnaire, Neurology (clinical), cardiovascular autonomic function tests, disorders of consciousness (other than epilepsy), neurological disorder, Survey, Laboratorie, Human
Abstract

© 2022 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes., Background and purpose: Disorders of the autonomic nervous system (ANS) are common conditions, but it is unclear whether access to ANS healthcare provision is homogeneous across European countries. The aim of this study was to identify neurology-driven or interdisciplinary clinical ANS laboratories in Europe, describe their characteristics and explore regional differences. Methods: We contacted the European national ANS and neurological societies, as well as members of our professional network, to identify clinical ANS laboratories in each country and invite them to answer a web-based survey. Results: We identified 84 laboratories in 22 countries and 46 (55%) answered the survey. All laboratories perform cardiovascular autonomic function tests, and 83% also perform sweat tests. Testing for catecholamines and autoantibodies are performed in 63% and 56% of laboratories, and epidermal nerve fiber density analysis in 63%. Each laboratory is staffed by a median of two consultants, one resident, one technician and one nurse. The median (interquartile range [IQR]) number of head-up tilt tests/laboratory/year is 105 (49-251). Reflex syncope and neurogenic orthostatic hypotension are the most frequently diagnosed cardiovascular ANS disorders. Thirty-five centers (76%) have an ANS outpatient clinic, with a median (IQR) of 200 (100-360) outpatient visits/year; 42 centers (91%) also offer inpatient care (median 20 [IQR 4-110] inpatient stays/year). Forty-one laboratories (89%) are involved in research activities. We observed a significant difference in the geographical distribution of ANS services among European regions: 11 out of 12 countries from North/West Europe have at least one ANS laboratory versus 11 out of 21 from South/East/Greater Europe (p = 0.021). Conclusions: This survey highlights disparities in the availability of healthcare services for people with ANS disorders across European countries, stressing the need for improved access to specialized care in South, East and Greater Europe.

Published
2022
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10. Retinal Thickness Predicts the Risk of Cognitive Decline in Parkinson Disease

Author

Fisiología, Neurociencias, Fisiologia, Neurozientziak, Murueta-Goyena Larrañaga, Ane, Del Pino Sáez, Rocío, Galdós Iztueta, Marta, Arana Larrea, Begoña, Acera, Marian, Carmona Abellán, Mar, Fernández Valle, Tamara, Tijero Merino, Beatriz, Lucas Jiménez, Olaia, Ojeda, Natalia, Ibarretxe Bilbao, Naroa, Peña, Javier, Cortés, Jesús M., Ayala Fernández, Unai, Barrenechea, Maitane, Gómez Esteban, Juan Carlos, Gabilondo Cuellar, Iñigo, Fisiología, Neurociencias, Fisiologia, Neurozientziak, Murueta-Goyena Larrañaga, Ane, Del Pino Sáez, Rocío, Galdós Iztueta, Marta, Arana Larrea, Begoña, Acera, Marian, Carmona Abellán, Mar, Fernández Valle, Tamara, Tijero Merino, Beatriz, Lucas Jiménez, Olaia, Ojeda, Natalia, Ibarretxe Bilbao, Naroa, Peña, Javier, Cortés, Jesús M., Ayala Fernández, Unai, Barrenechea, Maitane, Gómez Esteban, Juan Carlos, and Gabilondo Cuellar, Iñigo

Abstract

Objective This study was undertaken to analyze longitudinal changes of retinal thickness and their predictive value as biomarkers of disease progression in idiopathic Parkinson's disease (iPD). Methods Patients with Lewy body diseases were enrolled and prospectively evaluated at 3 years, including patients with iPD (n = 42), dementia with Lewy bodies (n = 4), E46K-SNCA mutation carriers (n = 4), and controls (n = 17). All participants underwent Spectralis retinal optical coherence tomography and Montreal Cognitive Assessment, and Unified Parkinson's Disease Rating Scale score was obtained in patients. Macular ganglion cell-inner plexiform layer complex (GCIPL) and peripapillary retinal nerve fiber layer (pRNFL) thickness reduction rates were estimated with linear mixed models. Risk ratios were calculated to evaluate the association between baseline GCIPL and pRNFL thicknesses and the risk of subsequent cognitive and motor worsening, using clinically meaningful cutoffs. Results GCIPL thickness in the parafoveal region (1- to 3-mm ring) presented the largest reduction rate. The annualized atrophy rate was 0.63 mu m in iPD patients and 0.23 mu m in controls (p < 0.0001). iPD patients with lower parafoveal GCIPL and pRNFL thickness at baseline presented an increased risk of cognitive decline at 3 years (relative risk [RR] = 3.49, 95% confidence interval [CI] = 1.10-11.1, p = 0.03 and RR = 3.28, 95% CI = 1.03-10.45, p = 0.045, respectively). We did not identify significant associations between retinal thickness and motor deterioration. Interpretation Our results provide evidence of the potential use of optical coherence tomography-measured parafoveal GCIPL thickness to monitor neurodegeneration and to predict the risk of cognitive worsening over time in iPD

Published
2021

11. Quantitative analysis of dysautonomia in patients with autonomic dysreflexia

Author

Neurociencias, Neurozientziak, Civicos Sánchez, Nora, Acera, Marian, Murueta-Goyena Larrañaga, Ane, Sagastibeltza Galarraga, Nagore, Martínez Rodríguez, Raquel, Cuadrado, Montserrat, Orueta, Arrate, Tijero Merino, Beatriz, Fernández Valle, Tamara, Del Pino Sáez, Rocío, Gabilondo Cuellar, Iñigo, Jauregui Abrisqueta, María Luisa, Gómez Esteban, Juan Carlos, Neurociencias, Neurozientziak, Civicos Sánchez, Nora, Acera, Marian, Murueta-Goyena Larrañaga, Ane, Sagastibeltza Galarraga, Nagore, Martínez Rodríguez, Raquel, Cuadrado, Montserrat, Orueta, Arrate, Tijero Merino, Beatriz, Fernández Valle, Tamara, Del Pino Sáez, Rocío, Gabilondo Cuellar, Iñigo, Jauregui Abrisqueta, María Luisa, and Gómez Esteban, Juan Carlos

Abstract

Autonomic dysreflexia (AD) is a life-threatening condition for individuals with cervical or high-thoracic spinal cord injury (SCI). The profile of autonomic dysfunction in AD using validated clinical autonomic tests has not been described so far, although it could be useful to identify SCI patients at greater risk of developing AD non-invasively. With this objective, 37 SCI patients (27% female) were recruited, and hemodynamic and cardiac parameters were continuously monitored to determine the presence of AD, defined as an increase of systolic blood pressure of 20 mmHg or higher after bladder filling with saline. Then, standard autonomic function testing was performed, including Deep Breathing, Valsalva Manoeuvre and Tilt Table Test. Finally, baroreflex sensitivity (BRS), and spectral analysis of heart rate and blood pressure variability were measured at rest. Catecholamines and vasopressin levels were also measured at supine and upright positions. The severity of SCI was assessed through clinical and radiological examinations. AD was observed in 73.3% of SCI patients, being 63.6% of them asymptomatic during the dysreflexive episode. AD patients displayed a drop in sympathetic outflow, as determined by decreased noradrenalin plasma levels, reduced sympathovagal balance and increased BRS. In line with decreased sympathetic activity, the incidence of neurogenic orthostatic hypotension was higher in AD patients. Our results provide novel evidence regarding the autonomic dysfunction in SCI patients with AD compared to non-AD patients, posing non-invasively measured autonomic parameters as a powerful clinical tool to predict AD in SCI patients.

Published
2021

12. Autonomic dysfunction is associated with neuropsychological and neuropsychiatric impairment in patients with Lewy body diseases

Author

Neurociencias, Neurozientziak, Del Pino Sáez, Rocío, Murueta-Goyena Larrañaga, Ane, Acera Gil, María Ángeles, Carmona Abellán, Mar, Tijero Merino, Beatriz, Lucas Jiménez, Olaia, Ojeda, Natalia, Ibarretxe Bilbao, Naroa, Peña Lasa, Javier, Gabilondo Cuellar, Iñigo, Gómez Esteban, Juan Carlos, Neurociencias, Neurozientziak, Del Pino Sáez, Rocío, Murueta-Goyena Larrañaga, Ane, Acera Gil, María Ángeles, Carmona Abellán, Mar, Tijero Merino, Beatriz, Lucas Jiménez, Olaia, Ojeda, Natalia, Ibarretxe Bilbao, Naroa, Peña Lasa, Javier, Gabilondo Cuellar, Iñigo, and Gómez Esteban, Juan Carlos

Abstract

Objective: This study aimed to analyze the association of autonomic dysfunction with cognition, depression, apathy, and fatigue in Lewy body disease (LBD). Methods: We included 61 patients [49 with idiopathic Parkinson’s disease, 7 with dementia with Lewy bodies, and 5 E46K- SNCA mutation carriers] and 22 healthy controls. All participants underwent a comprehensive battery of neuropsychologi- cal and clinical measures, autonomic symptom assessment with the SCOPA-AUT, analysis of non-invasive hemodynamic parameters during deep breathing, the Valsalva maneuver, and a 20-min tilt test, and electrochemical skin conductance measurement at rest (Sudoscan). Student’s t tests were used to assess group diferences, and bivariate correlations and stepwise linear regressions to explore associations between autonomic function, cognition, depression, apathy, and fatigue. Results: Compared to controls, patients who had signifcant impairment (p<0.05) in cognition, higher depression, apathy, and fatigue, more autonomic symptoms and objective autonomic dysfunction, reduced deep breathing heart rate variability [expiratory-to-inspiratory (E/I) ratio], prolonged pressure recovery time, and lower blood pressure in Valsalva late phase II and phase IV, while 24.1% had orthostatic hypotension in the tilt test. Autonomic parameters signifcantly correlated with cognitive and neuropsychiatric outcomes, systolic blood pressure during the Valsalva maneuver predicting apathy and depres- sion. The E/I ratio was the main predictor of cognitive performance (17.6% for verbal fuency to 32.8% for visual memory). Conclusion: Cardiovascular autonomic dysfunction is associated with cognitive and neuropsychiatric impairment in LBD, heart rate variability during deep breathing and systolic blood pressure changes during the Valsalva procedure are the main predictors of neuropsychological performance and depression/apathy symptoms, respectively.

Published
2020

13. Parafoveal thinning of inner retina is associated with visual dysfunction in Lewy body diseases

Author

Biología celular e histología, Neurociencias, Neurozientziak, Zelulen biologia eta histologia, Murueta-Goyena Larrañaga, Ane, Del Pino Sáez, Rocío, Reyero Lobo, Paula, Galdós Iztueta, Marta, Arana Larrea, Begoña, Lucas Jiménez, Olaia, Acera, Marian, Tijero Merino, Beatriz, Ibarretxe Bilbao, Naroa, Ojeda, Natalia, Pena, Javier, Cortés Díaz, Jesús María, Gómez Esteban, Juan Carlos, Gabilondo Cuellar, Iñigo, Biología celular e histología, Neurociencias, Neurozientziak, Zelulen biologia eta histologia, Murueta-Goyena Larrañaga, Ane, Del Pino Sáez, Rocío, Reyero Lobo, Paula, Galdós Iztueta, Marta, Arana Larrea, Begoña, Lucas Jiménez, Olaia, Acera, Marian, Tijero Merino, Beatriz, Ibarretxe Bilbao, Naroa, Ojeda, Natalia, Pena, Javier, Cortés Díaz, Jesús María, Gómez Esteban, Juan Carlos, and Gabilondo Cuellar, Iñigo

Abstract

Background Retinal optical coherence tomography findings in Lewy body diseases and their implications for visual outcomes remain controversial. We investigated whether region-specific thickness analysis of retinal layers could improve the detection of macular atrophy and unravel its association with visual disability in Parkinson's disease. Methods Patients with idiopathic Parkinson's disease (n = 63), dementia with Lewy bodies (n = 8), and E46K mutation carriers in the alpha-synuclein gene (E46K-SNCA) (n = 4) and 34 controls underwent Spectralis optical coherence tomography macular scans and a comprehensive battery of visual function and cognition tests. We computed mean retinal layer thicknesses of both eyes within 1-, 2-, 3-, and 6-mm diameter macular discs and in concentric parafoveal (1- to 2-mm, 2- to 3-mm, 1- to 3-mm) and perifoveal (3- to 6-mm) rings. Group differences in imaging parameters and their relationship with visual outcomes were analyzed. A multivariate logistic model was developed to predict visual impairment from optical coherence tomography measurements in Parkinson's disease, and cutoff values were determined with receiver operating characteristic analysis. Results When compared with controls, patients with dementia with Lewy bodies had significant thinning of the ganglion cell-inner plexiform layer complex within the central 3-mm disc mainly because of differences in 1- to 3-mm parafoveal thickness. This parameter was strongly correlated in patients, but not in controls, with low contrast visual acuity and visual cognition outcomes (P < .05, False Discovery Rate), achieving 88% of accuracy in predicting visual impairment in Parkinson's disease. Conclusion Our findings support that parafoveal thinning of ganglion cell-inner plexiform complex is a sensitive and clinically relevant imaging biomarker for Lewy body diseases, specifically for Parkinson's disease. (c) 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf

Published
2019

14. Impacto de la estimulación subtalámica a largo plazo sobre la situación cognitiva de los pacientes con enfermedad de Parkinson avanzada

Author

Cirugía, radiología y medicina física, Neurociencias, Kirurgia,erradiologia eta medikuntza fisikoa, Neurozientziak, Acera, Marian, Molano Salazar, Ana, Tijero Merino, Beatriz, Bilbao Barandica, Gaizka, Lambarri, Imanol, Villoria, Rafael, Somme, Johanne, Ruiz de Gopegui, E., Gabilondo Cuellar, Iñigo, Gómez Esteban, Juan Carlos, Cirugía, radiología y medicina física, Neurociencias, Kirurgia,erradiologia eta medikuntza fisikoa, Neurozientziak, Acera, Marian, Molano Salazar, Ana, Tijero Merino, Beatriz, Bilbao Barandica, Gaizka, Lambarri, Imanol, Villoria, Rafael, Somme, Johanne, Ruiz de Gopegui, E., Gabilondo Cuellar, Iñigo, and Gómez Esteban, Juan Carlos

Abstract

Objetivo El objetivo es evaluar los efectos de la estimulación cerebral profunda del núcleo subtalámico bilateral (STN-DBS) sobre el estado cognitivo de los pacientes con enfermedad de Parkinson 5 años después de la cirugía. Materiales y métodos En este estudio prospectivo se incluyeron 50 pacientes con enfermedad de Parkinson (62,5% hombres, edad media 62,2 ± 8,2 años y duración de la enfermedad 14,1 ± 6,3 años) sometidos a STN-DBS. Todos los pacientes fueron evaluados preoperatoriamente y un año después de la cirugía, y 40 pacientes fueron seguidos hasta 5 años. En cada visita se realizaron las siguientes evaluaciones neuropsicológicas: Mini-Mental State Examination, Mattis Dementia Rating Scale (MDRS), test de secuencias números-letras de WAIS III-LN, Prueba de dibujo de reloj, Prueba de aprendizaje verbal auditivo Rey, la Prueba de retención visual de Benton, la Prueba de juicio de orientación de línea de Benton, la fluidez verbal fonética y semántica, la Prueba Stroop y la Escala de clasificación de depresión de Montgomery-Asberg. Resultados Anualmente se observaron reducciones en la puntación de Mini-Mental State Examination (–0,89%), Prueba del dibujo de reloj (–2,61%) y MDRS (–1,72%), fueron más marcados tanto para la fluidez verbal fonética (–13,28%) como semántica (–12,40%). Para la Prueba de aprendizaje verbal auditivo Rey observamos un deterioro en la capacidad de recuerdo diferido (–10,12%) un año después de la cirugía. A los 5 años la mayor parte del deterioro se produjo en la fluidez verbal, con reducciones adicionales de 16,10% y 16,60% para la fluidez verbal semántica y fonética, respectivamente. Se observó un empeoramiento más moderado del recuerdo inmediato (–16,87%), WAIS III-LN (–16,67%) y de la prueba de orientación lineal de Benton (–11,56%). Discusión La STN-DBS no condujo a deterioro cognitivo global a los 5 años de la cirugía. Hubo un deterioro significativo en la función verbal desde el primer año de la cirugía. El deterioro de la capacida

Published
2019

15. Small fiber neuropathy and phosphorylated alpha-synuclein in the skin of E46K- SNCA mutation carriers

Author

Neurociencias, Neurozientziak, Carmona Abellán, Mar, Gabilondo Cuellar, Iñigo, Murueta-Goyena Larrañaga, Ane, Khurana, Vikhram, Tijero Merino, Beatriz, Luquín, María Rosario, Acera, Marian, Del Pino Sáez, Rocío, Gardeazabal García, Jesús, Martínez-Valbuena, Iván, Sánchez-Pernaute, Rosario, Gómez Esteban, Juan Carlos, Neurociencias, Neurozientziak, Carmona Abellán, Mar, Gabilondo Cuellar, Iñigo, Murueta-Goyena Larrañaga, Ane, Khurana, Vikhram, Tijero Merino, Beatriz, Luquín, María Rosario, Acera, Marian, Del Pino Sáez, Rocío, Gardeazabal García, Jesús, Martínez-Valbuena, Iván, Sánchez-Pernaute, Rosario, and Gómez Esteban, Juan Carlos

Abstract

Background and objective: In 2004 we described the E46K mutation in alpha-synuclein gene (E46K-SNCA), a rare point mutation causing an aggressive Lewy body disease with early prominent non-motor features and small fiber denervation of myocardium. Considering the potential interest of the skin as a target for the development of biomarkers in Parkinson's Disease (PD), in this work we aimed to evaluate structural and functional integrity of small autonomic nerve fibers and phosphorylated alpha-synuclein (p-synuclein) deposition in the skin of E46K- SNCA carriers as compared to those observed in parkin gene mutation (PARK2) carriers and healthy controls. Patients and methods: We studied 7 E46K-SNCA carriers (3 dementia with Lewy bodies, 2 pure autonomic failure, 1 PD and 1 asymptomatic), 2 PARK2 carriers and 2 healthy controls to quantify intraepidermal nerve fiber density and p-synuclein deposition with cervical skin punch biopsies (immunohistochemistry against anti PGP9.5/UCHL-1, TH and p-synuclein) and sudomotor function with electrochemical skin conductance (ESC) (SudoScan). Results: All E46K-SNCA carriers had moderate to severe p-synuclein deposits and small fiber neurodegeneration in different epidermal and dermal structures including nerve fascicles and glands, especially in carriers with Pure Autonomic Failure, while p-synuclein aggregates where absent in healthy controls and in one of two PARK2 carriers. The severity of the latter skin abnormalities in E46K-SNCA were correlated with sudomotor dysfunction (lower ESC) in hands (p = 0.035). Interpretation: These results together with our previous findings support the relevance of E46K-SNCA mutation as a suitable model to study small fiber neuropathy in Lewy body diseases.

Published
2019

16. Myocardial MIBG scintigraphy in genetic Parkinson’s disease as a model for Lewy body disorders

Author

Neurociencias, Neurozientziak, Gabilondo Cuellar, Iñigo, Llorens, Verónica, Rodríguez, Trinidad, Fernández Martínez, Manuel, Pérez Concha, Tomás, Acera Gil, María Ángeles, Tijero Merino, Beatriz, Murueta-Goyena Larrañaga, Ane, Del Pino Sáez, Rocío, Cortés Díaz, Jesús María, Gómez Esteban, Juan Carlos, Neurociencias, Neurozientziak, Gabilondo Cuellar, Iñigo, Llorens, Verónica, Rodríguez, Trinidad, Fernández Martínez, Manuel, Pérez Concha, Tomás, Acera Gil, María Ángeles, Tijero Merino, Beatriz, Murueta-Goyena Larrañaga, Ane, Del Pino Sáez, Rocío, Cortés Díaz, Jesús María, and Gómez Esteban, Juan Carlos

Abstract

Purpose To identify myocardial sympathetic denervation patterns suggestive of Lewy body (LB) pathology in patients with genetic and idiopathic parkinsonisms by 123I-metaiodobenzylguanidine (MIBG) scintigraphy. Methods We retrospectively analysed myocardial MIBG images acquired with a dual-head gamma camera and low-energy high- resolution collimator (LEHR) in 194 patients with suspected synucleinopathy or atypical parkinsonism, including 34 with genetic Parkinson’s disease (PD; 4 PARK1, 8 PARK2 and 22 PARK8), 85 with idiopathic PD (iPD), 6 with idiopathic REM sleep behaviour disorder (iRBD), 17 with dementia with LB (DLB), 40 with multiple system atrophy (MSA) and 12 with progressive supranuclear palsy (PSP), and in 45 healthy controls. We calculated heart-to-mediastinum MIBG uptake ratios (HMR) at 15 min and 4 h (HMR4H) for the LEHR and standardized medium-energy collimators, to obtain classification accuracies and optimal cut-off values for HMR using supervised classification and ROC analyses. Results While patients with LB disorders had markedly lower HMR4HLEHR than controls (controls 1.86 ± 0.26, iPD 1.38 ± 0.29, iRBD 1.23 ± 0.09, PARK1 1.20 ± 0.09, DLB 1.17 ± 0.11; p < 0.05), for the remaining patient categories differences were smaller (PARK8 1.51 ± 0.32; p < 0.05) or not significant (MSA 1.82 ± 0.37, PSP 1.59 ± 0.23, PARK2 1.51 ± 0.30; p > 0.05). The diag- nostic accuracy of HMR4HLEHR was highest in patients with LB disorders (PARK1, iPD, DLB, iRBD; 89% to 97%) and lowest in those with PARK2, PARK8, PSP and MSA (65% to 76%), with an optimal HMR4HLEHR cut-off value of 1.72 for discrim- inating most patients with LB disorders including iPD and 1.40 for discriminating those with aggressive LB spectrum phenotypes (DLB, PARK1 and iRBD). Conclusion Our study including patients with a wide spectrum of genetic and idiopathic parkinsonisms with different degrees of LB pathology further supports myocardial MIBG scintigraphy as an accurate tool for discriminating patient

Published
2018

23. Clinical manifestations of intermediate allele carriers in Huntington disease

Author

Cubo E., Ramos-Arroyo M. A., Martinez-Horta S., Martinez-Descalls A., Calvo S., Gil-Polo CAnne-Catherine Bachoud-Lévi, Anna Rita Bentivoglio, Ida Biunno, Raphael M Bonelli, Jean-Marc Burgunder, Stephen B Dunnett, Joaquim J Ferreira, Olivia J Handley, Arvid Heiberg, Torsten Illmann, G Bernhard Landwehrmeyer, Jamie Levey, Maria Ramos-Arroyo, Jørgen E Nielsen, Susana Pro Koivisto, Markku Päivärinta, Raymund A C Roos, Ana Rojo Sebastián, Sarah J Tabrizi, Wim Vandenberghe, Christine Verellen-Dumoulin, Tereza Uhrova, Jan Wahlström, Jacek Zaremba, Verena Baake, Katrin Barth, Adrien Come, Leonor Correia Guedes, Ana Maria Finisterra, Monica Bascuñana Garde, Reineke Bos, Sabrina Betz, Jenny Callaghan, Selene Capodarca, Sébastien Charpentier, Wildson Vieira da Silva, Martina Di Renzo, Daniel Ecker, Ruth Fullam, Camille Genoves, Mette Gilling, Carina Hvalstedt, Christine Held, Andrea Horta-Barba, Kerstin Koppers, Claudia Lamanna, Matilde Laurà, Asunción Martínez Descals, Saul Martinez-Horta, Tiago Mestre, Sara Minster, Daniela Monza, Lisanne Mütze, Martin Oehmen, Helene Padieu, Laurent Paterski, Nadia Peppa, Beate Rindal, Dawn Rogers, Niini Røren, Pavla Šašinková, Yuri Seliverstov, Catherine Taylor, Erika Timewell, Jenny Townhill, Patricia Trigo Cubillo, Marleen R van Walsem, Marie-Noelle Witjes-Ané, Grzegorz Witkowski, Abigail Wright, Elizaveta Yudina, Daniel Zielonka, Eugeniusz Zielonka, Paola Zinzi, Cécile Minet, Pascale Ribaï, Dominique Van Paemel, Lena Hjermind, Oda Jacobsen, Suzanne Lindquist, Jørgen Nielsen, Lisbeth Regeur, Jette Stockholm, Ida Unmack Larsen, Christina Vangsted-Hansen, Tua Vinther-Jensen, Pia Eklund, Heli Hiivola, Hannele Hypponen, Kirsti Martikainen, Katri Tuuha, Philippe Allain, Dominique Bonneau Marie Bost, Bénédicte Gohier, Marie-Anne Guérid, Audrey Olivier, Julie Prouzet, Adriana Prundean, Clarisse Scherer-Gagou, Christophe Verny, Blandine Babiloni, Sabrina Debruxelles, Charlotte Duché, Cyril Goizet, Laetitia Jameau, Danielle Lafoucrière, Umberto Spampinato, Anne-Catherine Bachoud-Lévi, Farideh Badei, Lotfi Boudali, Catherine Bourdet, Laurent Cléret, Maryline Couette, Cécile Focseneanu, Laurie Lemoine, Graça Morgado, Mehdi Sebaiti, Claire Thiriez, Laetitia Vervoitte, Katia Youssov, Jean-Philippe Azulay, Christelle Chabot, Marie Delfini, Alexandre Eusebio, Frédérique Fluchere, Christine Garreau, Aicha Ghenam, Hélène Grosjean, Laura Mundler, Marielle Nowak, Roland Raseta, Maïté Bertrand, Fabienne Calvas, Samia Cheriet, Laurent Marquine, Michèle Pierre, Jérémie Pariente, Sandrine Rolland, Alice Seris, Valérie Vaquie, Christoph Michael Kosinski, Eva Milkereit, Daniela Probst, Kathrin Reetz, Christian Sass, Johannes Schiefer, Christiane Schlangen, Cornelius J Werner, Gisa Ellrichmann, Lennard Herrmann, Rainer Hoffmann, Barbara Kaminski, Carsten Saft, Kai Boelmans, Christos Ganos, Ines Goerendt, Walburgis Heinicke, Ute Hidding, Jan Lewerenz, Alexander Münchau, Michael Orth, Jenny Schmalfeld, Lars Stubbe, Simone Zittel, Gabriele Diercks, Dirk Dressler, Flverly Francis, Sabine Gayde-Stephan, Heike Gorzolla, Bianca Kramer, Rebecca Minschke, Christoph Schrader, Pawel Tacik, Natalie Bechtel, Heike Beckmann, Stefan Bohlen, Nicole Göpfert, Eva Hölzner, Herwig Lange, Ralf Reilmann, Stefanie Rohm, Silke Rumpf, Sigrun Schepers, Nathalia Weber, Michael Bachmeier, Matthias Dose, Nina Hofstetter, Ralf Marquard, Alzbeta Mühlbäck, Andrea Buck, Julia Connemann, Carolin Geitner, Andrea Kesse, Bernhard Landwehrmeyer, Franziska Lezius, Solveig Nepper, Anke Niess, Ariane Schneider, Daniela Schwenk, Sigurd Süssmuth, Sonja Trautmann, Patrick Weydt, Stephan Klebe, Thomas Musacchio, Christine Leypold, Kerstin Nöth, Claudia Cormio, Marina de Tommaso, Anna Rita Dellomonaco, Olimpia Difruscolo, Giovanni Franco, Vittorio Sciruicchio, Claudia Serpino, Michela Figorilli, Francesco Marrosu, Antonella Muroni, Valeria Piras, Melisa Vacca, Caterina Bartoli, Elisabetta Bertini, Fernanda Fortunato, Elena Ghelli, Andrea Ginestroni, Claudia Mechi, Marco Paganini, Silvia Piacentini, Silvia Pradella, Anna Maria Romoli, Sandro Sorbi, Giuseppe De Michele, Luigi Di Maio, Carlo Rinaldi, Marco Massarelli, Silvio Peluso, Alessandro Roca, Cinzia Valeria Russo, Pierpaolo Sorrentino, Elena Salvatore, Tecla Tucci, Milena Cannella, Valentina Codella, Francesca De Gregorio, Annunziata De Nicola, Francesca Elifani, Tiziana Martino, Francesca Lovo, Irene Mazzante, Martina Petrollini, Maria Simonelli, Ferdinando Squitieri, Maurizio Vezza, Barbara D'Alessio, Chiara Esposito, Giulia Coarelli, Michela Ferraldeschi, Marina Frontali, Gioia Jacopini, Giovanni Ristori, Silvia Romano, Monique S E van Hout, Jeroen P P van Vugt, A Marit de Weert, Marloes Verhoeven, Simon J A van den Bogaard, Eve M Dumas, Ellen P 't Hart, Milou Jacobs, Anne Kampstra, Anne Schoonderbeek, Nils Olav Aanonsen, Olaf Aaserud, Liv Barnett, Kathrine Bjørgo, Nancy Borgerød, Elisabeth Dramstad, Madeleine Fannemel, Jan Frich, Helen Gundersen, Per Gørvell, Kathrine Haggag, Cecilie Haggag Johannessen, Lars Retterstøl, Oddveig Rosby, Jutta Rummel, Alma Sikiric, Olga Solberg, Marleen van Walsem, Ragnhild Wehus, Artur Dziadkiewicz, Agnieszka Konkel, Ewa Narożańska, Malgorzata Nowak, Piotr Robowski, Emilia Sitek, Jaroslaw Slawek, Witold Soltan, Michal Szinwelski, Michał Arkuszewski, Magdalena Błaszczyk, Magdalena Boczarska-Jedynak, Ewelina Ciach-Wysocka, Agnieszka Gorzkowska, Barbara Jasińska-Myga, Aleksandra Kaczmarczyk, Gabriela Kłodowska-Duda, Grzegorz Opala, Monika Rudzińska, Daniel Stompel, Krzysztof Banaszkiewicz, Dorota Boćwińska, Kamila Bojakowska-Jaremek, Małgorzata Dec, Natalia Grabska, Malgorzata Krawczyk, Ewelina Kubowicz, Michalina Malec-Litwinowicz, Agata Stenwak, Andrzej Szczudlik, Elżbieta Szczygieł, Magdalena Wójcik, Anna Wasielewska, Jacek Anioła Anna Bryl, Anna Ciesielska, Aneta Klimberg, Jerzy Marcinkowski, Husam Samara, Justyna Sempołowicz, Bartłomiej Wiśniewski, Anna Gogol, Piotr Janik, Zygmunt Jamrozik, Anna Kaminska, Hubert Kwiecinski, Jakub Antczak, Katarzyna Jachinska, Wioletta Krysa, Maryla Rakowicz, Przemyslaw Richter, Rafal Rola, Danuta Ryglewicz, Halina Sienkiewicz-Jarosz, Iwona Stępniak, Anna Sułek, Elzbieta Zdzienicka, Karolina Ziora-Jakutowicz, Cristina Januário, Filipa Júlio, Ana Salgueiro, Miguel Coelho, Tiago Mendes, Mário Miguel Rosa, Anabela Valadas, Cristina Semedo, Ana Calado, Joana Morgado, Margarida Dias, Manuel Almeida, Carmen Durán Herrera, Patrocinio Garcia Moreno, Jordi Bas, Núria Busquets, Matilde Calopa, Serge Jaumà Classen, Nadia Rodríguez Dedichá, Miquel Aguilar Barbera, Sonia Arribas Pardo, Dolors Badenes Guia, Noemi Calzado, Laura Casas Hernanz, Juan Pablo Tartari Díaz-Zorita, Judit López Catena, Pilar Quiléz Ferrer, Gemma Tome Carruesco, Misericordia Floriach Robert, Cèlia Mareca Viladrich, Elvira Roca, Jesús Miguel Ruiz Idiago, Antonio Villa Riballo, Antonia Campolongo, Ramon Fernandez de Bobadilla, Jaime Kulisevsky Bojarsky, Javier Pagonabarraga, Jesus Perez Perez, Carolina Villa, Maria Angeles Acera Gil, Koldo Berganzo Corrales, Juan Carlos Gomez Esteban, Amaia González, Beatriz Tijero Merino, Esther Cubo, Natividad Mariscal, Sandra Gutierrez Romero, José Matías Arbelo, Rocío Malo de Molina, Idaira Martín, Juan Manuel Periañez, Beatriz Udaeta, Fernando Alonso-Frech, Belén Frades, Marina Ávila Villanueva, Maria Ascension Zea Sevilla, Fernando Alonso Frech, María Del Mar Fenollar, Rocío García-Ramos García, Clara Villanueva, Mónica Bascuñana, Marta Fatás Ventura, Juan García Caldentey, Guillermo García Ribas, Justo García de Yébenes, José Luis López-Sendón Moreno, Verónica Mañanes Barral, Cici Feliz Feliz, Pedro José García Ruíz, Ana García, Rosa Guerrero López, Antonio Herranz Bárcenas, Asunción Martínez-Descals, Angel Martínez Pueyo, Veronica Puertas Martin, Noelia Rodríguez Martínez, María José Sainz Artiga, Vicenta Sánchez, Javier Del Val Fernandez, Carmen Antúnez Almagro, Salvadora Manzanares, Juan Marín Muñoz, María Martirio Antequera Torres, Fuensanta Noguera Perea, Laura Vivancos Moreau, Sonia González, Luis Menéndez Guisasola, Carlos Salvador, René Ribacoba, Pablo Sánchez Lozano, Marta Para Prieto, Aránzazu Gorospe, Inés Legarda Ramirez, Penelope Navas Arques, Monica Rodriguez Lopera, Barbara Vives Pastor, Itziar Gaston, Maria Antonia Ramos-Arroyo, Maria Dolores Martinez-Jaurrieta, José Manuel García Moreno, Carolina Mendez Lucena, José Chacón Peña, Fátima Damas Hermoso, Eva Pacheco Cortegana, Luis Redondo, Cristina Melgar Fernandez, Maite Paredes Mata, Maria Dolores Romero Lemos, Maria Bosca, Juan Andres Burguera, Francisco Castera Brugada Carmen Peiró Vilaplana, Elena Bellosta Diago, Javier López Del Val, Laura Martinez Martinez, Elena López, Peter Berglund, Radu Constantinescu, Gunnel Fredlund, Ulrika Høsterey-Ugander, Liselotte Neleborn-Lingefjärd, Yanik Stebler, Alain Kaelin, Irene Romero, Michael Schüpbach, Sabine Weber Zaugg, Lorna Downie, Roisin Jack, Kirsty Matheson, Zosia Miedzybrodzka, Daniela Rae, Sheila A Simpson, Fiona Summers, Alexandra Ure, Vivien Vaughn, Shahbana Akhtar, Jenny Crooks, Adrienne Curtis, Jenny de Souza, John Piedad, Hugh Rickards, Jan Wright, Elizabeth Coulthard, Louise Gethin, Beverley Hayward, Kasia Sieradzan, Monica Busse, Cynthia Butcher, Stephen Dunnett, Catherine Clenaghan, Sarah Hunt, Lesley Jones, Una Jones, Hanan Khalil, Michael Owen, Kathleen Price, Anne Rosser, Peter Brockie, Jillian Foster, Nicola Johns, Sue McKenzie, Jean Rothery, Gareth Thomas, Shona Yates, Alyson Andrew, Julie Frost, Rupert Noad, Jeremy Cosgrove, Deena Gallantree, Stephanie Hamer, Emma Hobson, Stuart Jamieson, Alison Kraus, Mandy Longthorpe, Ivana Markova, Hannah Musgrave, Caroline Peacy, Ashok Raman, Liz Rowett, Jean Toscano, Sue Wild, Carole Clayton, Pam Yardumian, Heather Dipple, Dawn Freire- Patino, Caroline Hallam, Julia Middleton, Uruj Anjum, Jan Coebergh, Charlotte Eddy, Nayana Lahiri, Meriel McEntagart, Michael Patton, Maria Peterson, Sarah Rose, Thomasin Andrews, Stefanie Brown, Stefania Bruno, Elvina Chu, Karen Doherty, Charlotte Golding, Salman Haider, Davina Hensman, Monica Lewis, Marianne Novak, Aakta Patel, Joy Read, Nicola Robertson, Elisabeth Rosser, Sarah Tabrizi, Rachel Taylor, Thomas Warner, Edward Wild, Natalie Arran, Judith Bek, David Craufurd, Marianne Hare, Liz Howard, Susan Huson, Liz Johnson, Mary Jones, Ashok Krishnamoorthy, Helen Murphy, Emma Oughton, Lucy Partington-Jones, Andrea Sollom, Julie Snowden, Cheryl Stopford, Jennifer Thompson, Iris Trender-Gerhard, Nichola Verstraelen, Leann Westmoreland, Ginette Cass, Lynn Davidson, Jill Davison, Neil Fullerton, Katrina Holmes, Suresh Komati, Sharon McDonnell, Zeid Mohammed, Karen Morgan, Lois Savage, Baldev Singh, Josh Wood, Andrea H Nemeth, Gill Siuda, Ruth Valentine, Kathryn Dixon, Richard Armstrong, David Harrison, Max Hughes, Sandra Large, John O Donovan, Amy Palmer, Andrew Parkinson, Beverley Soltysiak, Leanne Timings, Josh Williams, Oliver Bandmann, Alyson Bradbury, Helen Fairtlough, Kay Fillingham, Isabella Foustanos, Paul Gill, Mbombe Kazoka, Kirsty O'Donovan, Louise Nevitt, Oliver Quarrell, Cat Taylor, Katherine Tidswell, Lesley Gowers, Kingsley Powell, Pamela Bethwaite, Rachel Edwards, Kathleen Fuller, Michelle Phillips, Univ Angers, Okina, E., Cubo, M. A., Ramos-Arroyo, S., Martinez-Horta, A., Martinez-Descall, S., Calvo, CAnne-Catherine Bachoud-Lévi, Gil-Polo, Rita Bentivoglio, Anna, Biunno, Ida, M Bonelli, Raphael, Burgunder, Jean-Marc, B Dunnett, Stephen, J Ferreira, Joaquim, J Handley, Olivia, Heiberg, Arvid, Illmann, Torsten, Bernhard Landwehrmeyer, G, Levey, Jamie, Ramos-Arroyo, Maria, E Nielsen, Jørgen, Pro Koivisto, Susana, Päivärinta, Markku, C Roos, Raymund A, Rojo Sebastián, Ana, J Tabrizi, Sarah, Vandenberghe, Wim, Verellen-Dumoulin, Christine, Uhrova, Tereza, Wahlström, Jan, Zaremba, Jacek, Baake, Verena, Barth, Katrin, Come, Adrien, Correia Guedes, Leonor, Maria Finisterra, Ana, Bascuñana Garde, Monica, Bos, Reineke, Betz, Sabrina, Callaghan, Jenny, Capodarca, Selene, Charpentier, Sébastien, Vieira da Silva, Wildson, Di Renzo, Martina, Ecker, Daniel, Fullam, Ruth, Genoves, Camille, Gilling, Mette, Hvalstedt, Carina, Held, Christine, Horta-Barba, Andrea, Koppers, Kerstin, Lamanna, Claudia, Laurà, Matilde, Martínez 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Eve, P 't Hart, Ellen, Jacobs, Milou, Kampstra, Anne, Schoonderbeek, Anne, Olav Aanonsen, Nil, Aaserud, Olaf, Barnett, Liv, Bjørgo, Kathrine, Borgerød, Nancy, Dramstad, Elisabeth, Fannemel, Madeleine, Frich, Jan, Gundersen, Helen, Gørvell, Per, Haggag, Kathrine, Haggag Johannessen, Cecilie, Retterstøl, Lar, Rosby, Oddveig, Rummel, Jutta, Sikiric, Alma, Solberg, Olga, van Walsem, Marleen, Wehus, Ragnhild, Dziadkiewicz, Artur, Konkel, Agnieszka, Narożańska, Ewa, Nowak, Malgorzata, Robowski, Piotr, Sitek, Emilia, Slawek, Jaroslaw, Soltan, Witold, Szinwelski, Michal, Arkuszewski, Michał, Błaszczyk, Magdalena, Boczarska-Jedynak, Magdalena, Ciach-Wysocka, Ewelina, Gorzkowska, Agnieszka, Jasińska-Myga, Barbara, Kaczmarczyk, Aleksandra, Kłodowska-Duda, Gabriela, Opala, Grzegorz, Rudzińska, Monika, Stompel, Daniel, Banaszkiewicz, Krzysztof, Boćwińska, Dorota, Bojakowska-Jaremek, Kamila, Dec, Małgorzata, Grabska, Natalia, Krawczyk, Malgorzata, Kubowicz, Ewelina, Malec-Litwinowicz, Michalina, 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Barral, Verónica, Feliz Feliz, Cici, José García Ruíz, Pedro, García, Ana, Guerrero López, Rosa, Herranz Bárcenas, Antonio, Martínez-Descals, Asunción, Martínez Pueyo, Angel, Puertas Martin, Veronica, Rodríguez Martínez, Noelia, José Sainz Artiga, María, Sánchez, Vicenta, Del Val Fernandez, Javier, Antúnez Almagro, Carmen, Manzanares, Salvadora, Marín Muñoz, Juan, Martirio Antequera Torres, María, Noguera Perea, Fuensanta, Vivancos Moreau, Laura, González, Sonia, Menéndez Guisasola, Lui, Salvador, Carlo, Ribacoba, René, Sánchez Lozano, Pablo, Para Prieto, Marta, Gorospe, Aránzazu, Legarda Ramirez, Iné, Navas Arques, Penelope, Rodriguez Lopera, Monica, Vives Pastor, Barbara, Gaston, Itziar, Antonia Ramos-Arroyo, Maria, Dolores Martinez-Jaurrieta, Maria, Manuel García Moreno, José, Mendez Lucena, Carolina, Chacón Peña, José, Damas Hermoso, Fátima, Pacheco Cortegana, Eva, Redondo, Lui, Melgar Fernandez, Cristina, Paredes Mata, Maite, Dolores Romero Lemos, Maria, Bosca, Maria, Andres Burguera, Juan, Castera Brugada Carmen Peiró Vilaplana, Francisco, Bellosta Diago, Elena, López Del Val, Javier, Martinez Martinez, Laura, López, Elena, Berglund, Peter, Constantinescu, Radu, Fredlund, Gunnel, Høsterey-Ugander, Ulrika, Neleborn-Lingefjärd, Liselotte, Stebler, Yanik, Kaelin, Alain, Romero, Irene, Schüpbach, Michael, Weber Zaugg, Sabine, Downie, Lorna, Jack, Roisin, Matheson, Kirsty, Miedzybrodzka, Zosia, Rae, Daniela, A Simpson, Sheila, Summers, Fiona, Ure, Alexandra, Vaughn, Vivien, Akhtar, Shahbana, Crooks, Jenny, Curtis, Adrienne, de Souza, Jenny, Piedad, John, Rickards, Hugh, Wright, Jan, Coulthard, Elizabeth, Gethin, Louise, Hayward, Beverley, Sieradzan, Kasia, Busse, Monica, Butcher, Cynthia, Dunnett, Stephen, Clenaghan, Catherine, Hunt, Sarah, Jones, Lesley, Jones, Una, Khalil, Hanan, Owen, Michael, Price, Kathleen, Rosser, Anne, Brockie, Peter, Foster, Jillian, Johns, Nicola, Mckenzie, Sue, Rothery, Jean, Thomas, Gareth, Yates, Shona, Andrew, Alyson, Frost, Julie, Noad, Rupert, Cosgrove, Jeremy, Gallantree, Deena, Hamer, Stephanie, Hobson, Emma, Jamieson, Stuart, Kraus, Alison, Longthorpe, Mandy, Markova, Ivana, Musgrave, Hannah, Peacy, Caroline, Raman, Ashok, Rowett, Liz, Toscano, Jean, Wild, Sue, Clayton, Carole, Yardumian, Pam, Dipple, Heather, Freire- Patino, Dawn, Hallam, Caroline, Middleton, Julia, Anjum, Uruj, Coebergh, Jan, Eddy, Charlotte, Lahiri, Nayana, Mcentagart, Meriel, Patton, Michael, Peterson, Maria, Rose, Sarah, Andrews, Thomasin, Brown, Stefanie, Bruno, Stefania, Chu, Elvina, Doherty, Karen, Golding, Charlotte, Haider, Salman, Hensman, Davina, Lewis, Monica, Novak, Marianne, Patel, Aakta, Read, Joy, Robertson, Nicola, Rosser, Elisabeth, Tabrizi, Sarah, Taylor, Rachel, Warner, Thoma, Wild, Edward, Arran, Natalie, Bek, Judith, Craufurd, David, Hare, Marianne, Howard, Liz, Huson, Susan, Johnson, Liz, Jones, Mary, Krishnamoorthy, Ashok, Murphy, Helen, Oughton, Emma, Partington-Jones, Lucy, Sollom, Andrea, Snowden, Julie, Stopford, Cheryl, Thompson, Jennifer, Trender-Gerhard, Iri, Verstraelen, Nichola, Westmoreland, Leann, Cass, Ginette, Davidson, Lynn, Davison, Jill, Fullerton, Neil, Holmes, Katrina, Komati, Suresh, Mcdonnell, Sharon, Mohammed, Zeid, Morgan, Karen, Savage, Loi, Singh, Baldev, Wood, Josh, H Nemeth, Andrea, Siuda, Gill, Valentine, Ruth, Dixon, Kathryn, Armstrong, Richard, Harrison, David, Hughes, Max, Large, Sandra, O Donovan, John, Palmer, Amy, Parkinson, Andrew, Soltysiak, Beverley, Timings, Leanne, Williams, Josh, Bandmann, Oliver, Bradbury, Alyson, Fairtlough, Helen, Fillingham, Kay, Foustanos, Isabella, Gill, Paul, Kazoka, Mbombe, O'Donovan, Kirsty, Nevitt, Louise, Quarrell, Oliver, Taylor, Cat, Tidswell, Katherine, Gowers, Lesley, Powell, Kingsley, Bethwaite, Pamela, Edwards, Rachel, Fuller, Kathleen, Phillips, Michelle, Cubo, E., Ramos-Arroyo, M. A., Martinez-Horta, S., Martinez-Descalls, A., Russo, C. V., Calvo, S., Gil-Polo, C., Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Angers (UA), Ramos-Arroyo, María A., Martínez-Descalls, Asunción, Calvo, Sara, and Gil-Polo, Cecilia

Subjects
0301 basic medicine, Registrie, Adult, Male, medicine.medical_specialty, Aging, Heterozygote, Genetic counseling, Motor Disorders, Disease, Severity of Illness Index, 03 medical and health sciences, Cognition Disorder, 0302 clinical medicine, Trinucleotide Repeats, Internal medicine, medicine, Humans, Registries, Allele, Motor Disorder, Alleles, Huntingtin Protein, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, business.industry, Medicine (all), Trinucleotide Repeat, Cognition, Genetic Status, Middle Aged, Phenotype, Europe, Settore MED/26 - NEUROLOGIA, 030104 developmental biology, Huntington Disease, Case-Control Studies, Cohort, medicine (all), neurology (clinical), controlled clinical trial (topic), Quality of Life, Female, Neurology (clinical), business, Case-Control Studie, Cognition Disorders, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Human
Abstract

International audience; OBJECTIVE: There is controversy about the clinical consequences of intermediate alleles (IAs) in Huntington disease (HD). The main objective of this study was to establish the clinical manifestations of IA carriers for a prospective, international, European HD registry.METHODS: We assessed a cohort of participants at risk with RESULTS: Of 12,190 participants, 657 (5.38%) with CONCLUSIONS: Although aging worsened the UHDRS scores independently of the genetic status, IAs might confer a late-onset abnormal motor and cognitive phenotype. These results might have important implications for genetic counseling.CLINICALTRIALSGOV IDENTIFIER: NCT01590589.

Published
2016

24. Small fiber neuropathy in the post-COVID condition and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Clinical significance and diagnostic challenges.

Author

Azcue N, Teijeira-Portas S, Tijero-Merino B, Acera M, Fernández-Valle T, Ayala U, Barrenechea M, Murueta-Goyena A, Lafuente JV, de Munain AL, Ruiz-Irastorza G, Martín-Iglesias D, Gabilondo I, Gómez-Esteban JC, and Del Pino R

Subjects
Humans, Female, Male, Middle Aged, Adult, Post-Acute COVID-19 Syndrome, Clinical Relevance, Fatigue Syndrome, Chronic diagnosis, Fatigue Syndrome, Chronic physiopathology, Small Fiber Neuropathy diagnosis, Small Fiber Neuropathy physiopathology, COVID-19 complications
Abstract

Background: Patients with post-COVID condition (PCC) and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) experience symptoms potentially associated with small fiber neuropathy (SFN)., Methods: A sample of 90 participants, comprising 30 PCC patients, 30 ME/CFS patients, and 30 healthy controls (HC), matched by sex and age, was assessed. Neuropathic, autonomic, and fatigue symptoms were measured with TaskForce Monitor, the Sudoscan, heat and cold evoked potentials, In Vivo Corneal Confocal Microscopy (IVCCM), and specialized questionaries., Results: PCC and ME/CFS patients demonstrated significantly higher levels of autonomic symptoms (H = 39.89, p < 0.001), neuropathic symptoms (H = 48.94, p < 0.001), and fatigue (H = 49.29, p < 0.001) compared to HC. Quantitative sensory testing revealed significant differences in heat detection thresholds between PCC patients and HC (F = 4.82; p < 0.01). Regarding corneal small fiber tortuosity, there were statistically significant differences between patients and HC (F = 6.80; p < 0.01), indicating pathological responses in patients. Small fiber tortuosity in IVCCM was identified as the main discriminator between patients and HC (AUC = 0.720; p < 0.01)., Conclusion: PCC and ME/CFS patients demonstrated sensory SFN, as evidenced by impaired heat detection and increased tortuosity of small fibers in the central corneal subbasal plexus. The findings underscore the importance of a multimodal approach to comprehensively detect and characterize SFN. This study provides valuable scientific insights into the neuropathic manifestations associated with these conditions., (© 2025 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Published
2025
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