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Background It remains unknown whether the presence of coronary microcirculatory dysfunction (CMD) correlates with its equivalent condition in the brain, cerebral small vessel disease (CSVD). The cerebral-coronary connection (C3), a prospective blinded study, investigated the prevalence of CMD in patients with coronary artery disease (CAD) and its association with CSVD and cognitive function. Methods and results Patients with documented CAD fulfilling inclusion criteria underwent physiological assessment of epicardial vessels and the microcirculation using intracoronary pressure and Doppler. Coronary microcirculation-related indices included coronary flow reserve (CFR) and hyperaemic microvascular resistance. Brain magnetic resonance imaging, transcranial Doppler (TCD), and neurocognitive examination were performed. Overall, 67 patients were included in the study (mean age 66 years, 73% female). Patients with abnormal CFR ( Conclusions Coronary microcirculatory dysfunction is frequent in patients with CAD and correlates with CSVD, abnormal cerebral flow haemodynamics, and significant cognitive impairment. These findings support the hypothesis that microvascular dysfunction in the heart and the brain are part of a single pathological process affecting microcirculation in patients with CAD. Clinical Trial Registration ClinicalTrials.gov NCT04131075.

Objective:Cognitive processes underlying verbal and design fluency, and their neural correlates in patients with Alzheimer’s disease (AD) and behavioural variant Frontotemporal Dementia (bvFTD) remain unclear. We hypothesised that verbal and design fluency may be associated with distinct neuropsychological processes in AD and FTD, showing different patterns of impairment and neural basis.Methods:We enrolled 142 participants including patients with AD (n = 80, mean age = 74.71), bvFTD (n = 34, mean age = 68.18), and healthy controls (HCs) (n = 28, mean age = 71.14), that underwent cognitive assessment and 18F-fluorodeoxyglucose positron emission tomography imaging.Results:Semantic and phonemic fluency showed the largest effect sizes between groups, showing lower scores in bvFTD than AD and HCs, and lower scores in AD than HC. Both AD and bvFTD showed a lower number of unique designs in design fluency in comparison to HC. Semantic fluency was correlated with left frontotemporal lobe in AD, and with left frontal, caudate, and thalamus in bvFTD. Percentage of unique designs in design fluency was associated with the metabolism of the bilateral fronto-temporo-parietal cortex in AD, and the bilateral frontal cortex with right predominance in bvFTD. Repetitions in AD were correlated with bilateral frontal, temporal, and parietal lobes, and with left prefrontal cortex in bvFTD.Conclusions:Our findings demonstrate differential underlying cognitive processes in verbal and design fluency in AD and bvFTD. While memory and executive functioning associated with fronto-temporo-parietal regions were key in AD, attention and executive functions correlated with the frontal cortex and played a more significant role in bvFTD during fluency tasks.

We aimed to evaluate the frequency and mortality of COVID-19 in patients with Alzheimer’s disease (AD) and frontotemporal dementia (FTD). We conducted an observational case series. We enrolled 204 patients, 15.2% of whom were diagnosed with COVID-19, and 41.9% of patients with the infection died. Patients with AD were older than patients with FTD (80.36±8.77 versus 72.00±8.35 years old) and had a higher prevalence of arterial hypertension (55.8% versus 26.3%). COVID-19 occurred in 7.3% of patients living at home, but 72.0% of those living at care homes. Living in care facilities and diagnosis of AD were independently associated with a higher probability of death. We found that living in care homes is the most relevant factor for an increased risk of COVID-19 infection and death, with AD patients exhibiting a higher risk than those with FTD.

Introduction Numerous genetic variants have been associated with susceptibility to multiple sclerosis (MS). Variants located in genes involved in specific pathways, such as those affecting TNF‐α, can contribute to the risk of MS. The purpose of this study was to determine whether variants of these genes are associated with greater risk of MS. Methods We used whole‐exome sequencing to study genes coding for TNF‐α receptors and ligands, and proteins promoting TNF‐α expression in 116 individuals from 19 families including at least two MS patients. We compared patients with MS, patients with other autoimmune diseases, and healthy individuals. Results Greater polymorphism was observed in several genes in families with familial MS compared to the general population; this may reflect greater susceptibility to autoimmune diseases. Pedigree analysis also revealed that LT‐α variants rs1041981 and rs2229094 and LT‐β variant rs4647197 were associated with MS and that LT‐β variant rs4647183 was associated with other autoimmune diseases. The association between autoimmune disease and TNFAIP2 variant rs1132339 is particularly noteworthy, as is the fact that TNFAIP6 variant rs1046668 appears to follow a recessive inheritance pattern. Conclusions Our findings support the idea that the risk of familial MS is associated with variants of signaling pathways, including those involving TNF‐α., Pathways affecting TNF‐α are involved in immune signaling. Whole‐exome sequencing in 116 members of 19 families including at least two patients with multiple sclerosis was performed. Several nonsynonymous variants in TNF‐α pathways were found. The findings support the idea that the risk of familial MS is associated with variants of TNF‐α signaling pathways.

Resumen: Introducción: La enfermedad de Alexander es una enfermedad rara causada por mutaciones en el gen que codifica la proteína glial ácida fibrilar (GFAP). En un estudio previo hemos observado que la diferenciación de neuroesferas transfectadas con estas mutaciones genera un tipo celular que comparte la expresión de GFAP y NG2. Objetivos: Determinar el efecto de las mutaciones en marcadores moleculares en comparación con células de glioma diferenciados que expresan simultáneamente GFAP y NG2. Métodos: Se utilizaron muestras de glioblastoma humana (GLM) y neuroesferas procedentes de rata transfectadas con mutaciones de GFAP para el análisis de la expresión tras diferenciación de GFAP y NG2, así como el análisis inmunocitoquímico de diferenciación de ambos tipos celulares y detección de ambas proteínas, junto a nestina, vimentina, Olig2 y caspasa 3 a los 3 y 7 días de diferenciación. Resultados: Tanto las células transfectadas con mutaciones de GFAP como las células procedentes de GLM mostraron un incremento de NG2 y GFAP. Sin embargo, la expresión de células caspasa 3 positiva era marcadamente mayor entre las células transfectadas que entre las células procedentes de GLM. Conclusión: Nuestros resultados parecen indicar que la expresión de GFAP no es el único factor que condiciona la muerte celular en la enfermedad de Alexander y que la expresión de caspasa 3 y el potencial papel de la NG2 en incrementar la resistencia a la apoptosis en las células que coexpresan GFAP y NG2 deben ser considerados en la búsqueda de acciones terapéuticas en esta enfermedad. Abstract: Introduction: Alexander disease is a rare disorder caused by mutations in the gene coding for glial fibrillary acidic protein (GFAP). In a previous study, differentiation of neurospheres transfected with these mutations resulted in a cell type that expresses both GFAP and NG2. Objective: To determine the effect of molecular marker mutations in comparison to undifferentiated glioma cells simultaneously expressing GFAP and NG2. Methods: We used samples of human glioblastoma (GBM) and rat neurospheres transfected with GFAP mutations to analyse GFAP and NG2 expression after differentiation. We also performed an immunocytochemical analysis of neuronal differentiation for both cell types and detection of GFAP, NG2, vimentin, Olig2, and caspase-3 at 3 and 7 days from differentiation. Results: Both the cells transfected with GFAP mutations and GBM cells showed increased NG2 and GFAP expression. However, expression of caspase-3–positive cells was found to be considerably higher in transfected cells than in GBM cells. Conclusions: Our results suggest that GFAP expression is not the only factor associated with cell death in Alexander disease. Caspase-3 expression and the potential role of NG2 in increasing resistance to apoptosis in cells co-expressing GFAP and NG2 should be considered in the search for new therapeutic strategies for the disease.

It has been suggested that some individuals may present genetic susceptibility to SARS‐CoV‐2 infection, with particular research interest in variants of the ACE2 and TMPRSS2 genes, involved in viral penetration into cells, in different populations and geographic regions, although insufficient information is currently available. This study addresses the apparently reasonable hypothesis that variants of these genes may modulate viral infectivity, making some individuals more vulnerable than others. Through whole‐exome sequencing, the frequency of exonic variants of the ACE2, TMPRSS2, and Furin genes was analyzed in relation to presence or absence of SARS‐CoV‐2 infection in a familial multiple sclerosis cohort including 120 individuals from Madrid. The ACE2 gene showed a low level of polymorphism, and none variant was significantly associated with SARS‐CoV‐2 infection. These variants have previously been detected in Italy. While TMPRSS2 is highly polymorphic, the variants found do not coincide with those described in other studies, with the exception of rs75603675, which may be associated with SARS‐CoV‐2 infection. The synonymous variants rs61735792 and rs61735794 showed a significant association with infection. Despite the limited number of patients with SARS‐CoV‐2 infection, some variants, especially in TMPRSS2, may be associated with COVID‐19.

Background: Series of patients with SARS‐CoV‐2 infection report headache in 6%‐15% of cases, although some data suggest that the actual frequency is higher, and that headache is not associated with fever. No study published to date has analyzed the characteristics of headache in these patients. Objective: To analyze the characteristics of COVID‐19 related headaches. Methods: We conducted a survey of Spaniard healthcare professionals who have been infected by SARS‐CoV‐2 and presented headache during the course of the disease. The survey addressed respondents’ medical history and headache characteristics, and we analyzed the association between both. Results: We analyzed the responses of a sample of 112 healthcare professionals. History of migraine was reported by 20/112 (17.9%) of respondents, history of tension‐type headache by 8/112 (7.1%), and history of cluster headache was reported by a single respondent; 82/112(73.2%) of respondents had no history of headache. Headache presented independently of fever, around the third day after symptom onset. The previous history of migraine was associated with a higher frequency of pulsating headache (20% in patients with previous migraine vs 4.3% in those with no history of migraine, P = .013). Conclusion: Headache is often holocranial, hemicranial, or occipital, pressing, and worsens with physical activity or head movements. Because the characteristics of the headache and the associated symptoms are heterogeneous in our survey, we suggest that several patterns with specific pathophysiological mechanisms may underlie the headache associated with COVID‐19.

Resumen: Introducción: La pandemia de Covid-19 ha supuesto la necesidad de tomar decisiones para mantener la asistencia neurológica, sin precedentes. En este artículo se analiza esa toma de decisiones operativas. Desarrollo: Los autores refieren las fórmulas empleadas como son la realización de un plan de reorganización funcional, estrategias para la hospitalización y urgencias, la realización de consultas telefónicas para el mantenimiento de la atención neurológica, la asistencia en un área externa al hospital para pacientes preferentes, las decisiones sobre exploraciones complementarias y tratamientos intrahospitalarios periódicos o implantar un teléfono para la priorización de crisis epilépticas. Conclusión: A pesar de la situación de aislamiento, los servicios de neurología deben mantener la atención de sus pacientes a través de distintas fórmulas operativas, que como cualquier elemento de gestión, deberán evaluarse. Abstract: Introduction: The COVID-19 epidemic has led to the need for unprecedented decisions to be made to maintain the provision of neurological care. This article addresses operational decision-making during the epidemic. Development: We report the measures taken, including the preparation of a functional reorganisation plan, strategies for hospitalisation and emergency management, the use of telephone consultations to maintain neurological care, provision of care at a unit outside the hospital for priority patients, decisions about complementary testing and periodic in-hospital treatments, and the use of a specific telephone service to prioritise patients with epileptic seizures. Conclusion: Despite the situation of confinement, neurology departments must continue to provide patient care through different means of operation. Like all elements of management, these must be evaluated.

Introduction: The COVID-19 pandemic will give rise to long-term changes in neurological care, which are not easily predictable. Material and methods: A key informant survey was used to enquire about the changes expected in the specialty over the next 5 years. The survey was completed by heads of neurology departments with broad knowledge of the situation, having been active during the pandemic. Results: Despite a low level of consensus between participants, there was strong (85%) and moderate consensus (70%) about certain subjects, mainly the increase in precautions to be taken, the use of telemedicine and teleconsultations, the reduction of care provided in in-person consultations to avoid the presence of large numbers of people in waiting rooms, the development of remote training solutions, and the changes in monitoring visits during clinical trials. There was consensus that there would be no changes to the indication of complementary testing or neurological examination. Conclusion: The key informant survey identified the foreseeable changes in neurological care after the pandemic. Resumen: Introducción: La pandemia de COVID-19 va a conllevar cambios en la asistencia neurológica, que no se pueden prever fácilmente a largo plazo. Material y métodos: A través de un modelo de informadores clave se busca el consenso de cómo va a ser la especialidad en un plazo de 5 años, siendo los encuestados jefes de servicio de neurología con conocimiento amplio de la situación al haber actuado durante la pandemia. Resultados: Aunque se obtiene un grado de acuerdo bajo entre los encuestados, sí se describen acuerdos por consenso a nivel mayor (85%) y menor (70%). Los principales acuerdos se refieren al incremento de precauciones, al uso de la telemedicina, al mantenimiento de las consultas telefónicas, a la reducción de asistencia a las consultas evitando que hayan salas de espera con un número alto de personas, al desarrollo de técnicas docentes no presenciales y a la adaptación en el desarrollo de ensayos clínicos en relación con la visita de los monitores. Sin embargo, no se acuerda que haya cambios en la indicación de exploraciones complementarias, ni en la propia exploración neurológica. Conclusión: El método de informadores clave ha permitido conocer qué cambios se pueden prever tras la pandemia.

Introduction: There is growing evidence that SARS-CoV-2 can gain access to the central nervous system (CNS). We revise the literature on coronavirus infection of the CNS associated with neurological diseases. Development: Neurological symptoms were rarely reported in the SARS-CoV and MERS-CoV epidemics, although isolated cases were described. There are also reports of cases of neurological symptoms associated with CoV-OC43 and CoV-229E infection. The presence of neurological lesions, especially demyelinating lesions in the mouse hepatitis virus model, may explain the mechanisms by which coronaviruses enter the CNS, particularly those related with the immune response. This may explain the presence of coronavirus in patients with multiple sclerosis. We review the specific characteristics of SARS-CoV-2 and address the question of whether the high number of cases may be associated with greater CNS involvement. Conclusion: Although neurological symptoms are not frequent in coronavirus epidemics, the high number of patients with SARS-CoV-2 infection may explain the presence of the virus in the CNS and increase the likelihood of early- or delayed-onset neurological symptoms. Follow-up of patients affected by the SARS-CoV-2 epidemic should include careful assessment of the CNS. Resumen: Introducción: Diversas evidencias sugieren que el SARS-CoV-2 puede penetrar en el sistema nervioso central (SNC). Los autores revisan los datos de la literatura sobre los hallazgos de coronavirus en el SNC asociado a enfermedades neurológicas. Desarrollo: En las distintas epidemias con SARS-CoV y MERS-CoV la presencia de cuadros neurológicos es baja, pero se describen cuadros aislados de pacientes. También existen casos asociados a OC43-CoV y 229E-CoV. La existencia de lesiones neurológicas, especialmente desmielinizantes en el modelo MHV-CoV pueden explicar mecanismos de penetración de los CoV en el SNC y especialmente aquellos relacionados con la respuesta inmune, que puede justificar la existencia de CoV en pacientes con esclerosis múltiple. Los autores revisan aspectos diferenciales de SARS-CoV-2 y se plantean si debido al alto número de infectados, el virus puede afectar de forma mayor al SNC. Conclusión: Aunque la presencia de síntomas neurológicos en las epidemias de CoV es baja, la mayor frecuencia de infectados por SARS-CoV-2 podría justificar el paso del virus y la posibilidad de clínica neurológica precoz o tardía con mayor incidencia. El seguimiento de los pacientes de la epidemia debe atender con cuidado a la evaluación del SNC.

Fatigue is one of the most common symptoms in neurology, especially in MS patients with a prevalence of 65%. It is described as the most disabling symptom by 40% of MS patients. This study aimed to validate the Functional Assessment of Chronic Illness Therapy fatigue version (FACIT-F) and the F-2-MS scale, a new tool to distinguish between fatigue and fatigability.One hundred and fifteen patients with relapsing-remitting MS were enrolled. All patients completed a comprehensive neuropsychological battery, previously validated in MS. Fatigue was evaluated using the Fatigue Severity Scale (FSS), the Modified version of the Fatigue Impact Scale (MFIS), the Functional Assessment of Chronic Illness Therapy measure system (fatigue version) (FCIT-F), and a new tool for the assessment of fatigue and fatigability: the F-2-MS scale. Internal consistency was estimated with Cronbach's Alpha. For intergroup comparisons, Student's t-test and Pearson's chi-squared test were used. Pearson's correlation test was calculated for quantitative variables. Cohen's d was calculated to evaluate the effect size. Binary logistic regression was performed, considering the presence of fatigue as a criterion variable, and the FACIT-F and F-2-MS scores were added as predictor variables. ROC curves were also estimated. We conducted a confirmatory factor analysis for the F-2-MS scale, considering two latent factors.FACIT-F and F-2-MS showed high internal consistency. Both scales were highly correlated with MFIS and FSS, and showed a low correlation with Symbol Digit Modalities Test. There were significant differences between fatigued and non-fatigued patients on FACIT-F and F-2-MS scores with large effect sizes. Both scales showed AUC 0.90 and achieved a correct classification87%. Confirmatory factor analysis showed moderate evidence of two dimensions on the F-2-MS scale.The FACIT-F and F-2-MS scales showed appropriated psychometric properties to be used as fatigue measures in clinical and research settings, allowing a correct distinction between patients with and without fatigue, and contributing to the understanding of the complexities of fatigue in MS.

Background: Pause duration analysis is a common feature in the study of discourse in Alzheimer’s disease (AD) since this patient group has shown a consistent trend for longer pauses in comparison to healthy controls. This speech feature may also be helpful for early detection; however, studies involving patients at the pre-clinical, high-risk phase of amnestic mild cognitive impairment (aMCI) have yielded varying results. Objective: To characterize the probability density distribution of speech pause durations in 26 patients with AD, 57 amnestic multi-domain amnestic MCI patients (29 with memory encoding deficits, a-mdMCI-E, and 28 with retrieval impairment only, a-mdMCI-R) and 29 healthy controls (HC) in order assess whether there are significant differences between them. To explore the potential differences in pause production between patients with a-mdMCI-E and a-mdMCI-R, as the former are considered to be at higher risk of progressing to dementia. Methods: The 112 picture-based oral narratives obtained were manually transcribed and annotated for the automatic extraction and analysis of pause durations. Different probability distributions were tested for the fitting of pause durations while truncating shorter ranges. Recent findings in the field of Statistics were considered in order to avoid the inherent methodological uncertainty that this type of analysis entails by addressing the question of temporal thresholding and its potential repercussions on inter-annotator reliability in manual transcriptions. Results: A lognormal distribution (LND) explained the distribution of pause duration for all groups. Its fitted parameters (, ) followed a gradation from the group with shorter durations and a higher tendency to produce short pauses (HC) to the group with longer pause durations and a considerably higher tendency to produce long pauses with greater variance (AD). Importantly, a-mdMCI-E produced significantly longer pauses and with greater variability than their a-mdMCI-R counterparts (alpha=0.05). Conclusion: We report significant differences at the group level in pause distribution across all groups of study that could be used in future diagnostic tools and discuss the clinical implications of these findings, particularly regarding the characterization of a-mdMCI. This work is supported through a PhD grant awarded to P.P-D. by the banking Foundation ‘‘La Caixa’’ (ID 100010434, code: LCF/BQ/ES15/10360020). F.D-V. was supported by a grant awarded to project no. PID2019-107042GB-I00 (Ministerio de Ciencia e Innovación). A.H-F. and I.G.T. were supported by the grant no. TIN2017- 89244-R (MACDA) (Ministerio de Economia, Industria y Competitivi- dad, Gobierno de España) and the project PRO2020-S03 (RCO03080 Lingüística Quantitativa) of l’Institut d’Estudis Catalans. Peer Reviewed Objectius de Desenvolupament Sostenible::3 - Salut i Benestar

Background. We aimed to evaluate personality traits in patients with post-COVID syndrome, as well as the association with neuropsychiatric symptoms present in this disorder.Methods. The Big Five Structure Inventory was administered to 93 consecutive patients with a diagnosis of post-COVID syndrome and to matched controls. We also performed a comprehensive evaluation of depression, anxiety, fatigue, sleep quality, cognitive function, and olfactory function.Results. Patients with post-COVID syndrome scored lower for emotional stability, equanimity, positive mood, and self-control. Extraversion, emotional stability, and openness correlated negatively with anxiety and depression levels. Conscientiousness correlated negatively with anxiety. No statistically significant correlations were observed between personality traits and cognitive function, sleep quality, olfactory function, or fatigue. Personality scores explained 36.3% and 41% of the variance in scores on the anxiety and depression scales, respectively. Two personality profiles with lower levels of emotional stability were associated with depression and anxiety.Limitations. This study has a cross-sectional design, and personality was evaluated during post-COVID syndrome and not before the onset of the disease. Conclusions. Our study shows higher levels of neuroticism in patients with post-COVID syndrome. Personality traits were predictive of the presence of depression and anxiety, but not cognitive function, sleep quality, or fatigue, in the context of post-COVID syndrome. These findings may have implications for the detection of patients at risk of depression and anxiety in post-COVID syndrome, and for the development of preventive and therapeutic interventions.

The coronavirus disease 2019 (COVID-19) pandemic has caused a wide range of unprecedentedconsequences, including social, economic, and health disruptions. From the point of view ofhealthcare assistance, COVID-19 has deeply impacted usual practice at all levels since the beginningof 2020. In this setting, neurological assistance has adapted to the circumstances of the pandemic. Infact, because COVID-19 involves neurological symptoms, affected patients require the attention ofneurologists, and the high demand for clinical care entailed the recruitment ofmany neurologists tofrontline assistance (1). In addition, the pandemic has impacted the management of patients withneurological disorders, with changes in the management of relapses, usual follow-up, diagnosticprocedures, implementation or generalization of telemedicine, etc. Lockdown and social isolationwere also very harmful in patients with neurological disorders (2). Furthermore, the treatment ofneurological emergencies, such as stroke, was also compromised because of resource re-allocationduring the emergency, and the fear of patients to attend the hospital.The neurological community needed to share experiences about how to face this globalchallenge. Accordingly, this Research Topic was launched in April 2020 to address these issues.Over 117 manuscripts were submitted, and 76 papers have been published, including originals,reviews, and case reports. Studies have covered the main areas of neurological care, includinggeneral neurological care, stroke, epilepsy, multiple sclerosis, movement disorders, cognitiveneurology, neuromuscular disorders, headache, and neuropediatrics Fil: Matias Guiu, Jordi A.. Universidad Complutense de Madrid; España Fil: Sung, Sheng Feng. No especifíca; Fil: Hsieh, Cheng Yang. No especifíca; Fil: Nezu, Tomohisa. No especifíca; Fil: Porta Etessam, Jesús. Universidad Complutense de Madrid; España Fil: Allegri, Ricardo Francisco. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina

Oligodendrocyte precursor cell (OPC) migration is a mechanism involved in remyelination, these cells migrate from niches in the adult CNS. However, age and disease reduce the pool of OPCs, as a result, the remyelination capacity of the CNS decreases over time. Several experimental studies have introduced OPCs to the brain via direct injection or intrathecal administration. In this study, we used the nose-to brain pathway to deliver oligodendrocyte lineage cells (human oligodendroglioma (HOG) cells), which behave similarly to OPCs in vitro. To this end, we administered GFP-labelled HOG cells intranasally to experimental animals, which were subsequently euthanised at 30 or 60 days. Our results show that the intranasal route is a viable route to the CNS and that HOG cells administered intranasally migrate preferentially to niches of OPCs (clusters created during embryonic development and adult life). Our study provides evidence, albeit limited, that HOG cells either form clusters or adhere to clusters of OPCs in the brains of experimental animals.

Resumen Introduccion La esclerosis lateral amiotrofica (ELA) es una enfermedad neurodegenerativa, progresiva y de etiologia desconocida caracterizada por la degeneracion de motoneuronas superiores e inferiores. Aproximadamente el 90% de los casos de ELA son esporadicos, mientras que el 10% restante se consideran familiares. Independientemente de si son familiares o esporadicas, los pacientes desarrollan una debilidad progresiva, atrofia muscular con espasticidad y contracturas. Por lo general, la esperanza de vida en los pacientes de ELA es de 2 a 5 anos. Desarrollo Los modelos in vivo han ayudado a explicar la etiologia y la patogenesis, asi como los mecanismos de la ELA. Sin embargo, estos mecanismos no estan del todo esclarecidos aun, por lo que los modelos experimentales son fundamentales para continuar con el estudio de los mismos, asi como para la busqueda de posibles dianas terapeuticas. A pesar de que el 90% de los casos son esporadicos, la mayoria de los modelos utilizados hasta la actualidad para estudiar la patogenesis estan basados en las mutaciones geneticas asociadas a la enfermedad familiar, lo que provoca que la patogenesis de la ELA esporadica no sea aun conocida. Por tanto, seria fundamental el estudio de la enfermedad en modelos basados en la enfermedad esporadica. Conclusion En el presente articulo se han revisado los principales modelos experimentales, tanto geneticos como esporadicos, utilizados en el estudio de esta enfermedad, enfocandonos en los que se han desarrollado utilizando el roedor como plataforma experimental.

Objective. Recent evidence suggests that patients suffering post-acute COVID syndrome frequently report cognitive complaints, but their characteristics and pathophysiology are unknown. This study aims to determine the characteristics of cognitive dysfunction in patients reporting cognitive complaints after COVID-19 and to evaluate the correlation between cognitive function and anxiety, depression, sleep, and olfactory function.Methods. Cross-sectional study involving 50 patients with COVID-19 reporting cognitive complaints 9.12±3.46 months after the acute infection. Patients were evaluated with a comprehensive neuropsychological protocol, and scales of fatigue, depression, anxiety, sleep and an olfactory test. Normative data and an age- and education matched healthy control group were used for comparison. Results. COVID-19 patients showed a diminished performance on several tests evaluating attention and executive function, with alterations in processing speed, divided attention, selective attention, visual vigilance, intrinsic alertness, working memory, and inhibition; episodic memory; and visuospatial processing. Cognitive performance was correlated with olfactory dysfunction and sleep quality, but not with anxiety or depression.Conclusions. Patients with COVID-19 reporting cognitive symptoms showed a reduced cognitive performance, especially in the attention-concentration and executive functioning, episodic memory, and visuospatial processing domains. Future studies are necessary to disentangle the specific mechanisms associated with COVID-19 cognitive dysfunction.

BackgroundPrimary progressive aphasia (PPA) is a neurodegenerative syndrome for which no effective treatment is available. We aimed to assess the effect of repetitive transcranial magnetic stimulation (rTMS), using personalized targeting.MethodsWe conducted a randomized, double-blind, pilot study of patients with PPA receiving rTMS, with a subgroup of patients receiving active- versus control-site rTMS in a cross-over design. The primary outcome was changes in spontaneous speech (word count). Secondary outcomes included changes in other language tasks, global cognition, global impression of change, neuropsychiatric symptoms, and brain metabolism using FDG-PET.ResultsTwenty patients with PPA were enrolled (14 with nonfluent and 6 with semantic variant PPA). Compared to the control group, the group receiving active-site rTMS showed improvements in spontaneous speech, other language tasks, patient and caregiver global impression of change, apathy, and depression. This group also showed improvement or stabilization of results obtained in the baseline examination. Increased metabolism was observed in several brain regions after the therapy, particularly in the left frontal and parieto-temporal lobes and in the precuneus and posterior cingulate bilaterally.ConclusionsWe found an improvement in language, patient and caregiver perception of change, apathy, and depression using high frequency rTMS. The increase of regional brain metabolism suggests enhancement of synaptic activity with the treatment.Trial registrationNCT03580954 (clinicaltrials.gov). Registered 10 July 2018 (retrospectively registered).URL of the trial registry recordhttps://clinicaltrials.gov/ct2/show/NCT03580954

Resumen: Introducción: El uso de modelos experimentales en animales permite aumentar el conocimiento sobre la patología del sistema nervioso central. Sin embargo, en la esclerosis múltiple, no existe un modelo que permita una visión general de la enfermedad, de forma que es necesario utilizar una variedad de modelos que abarquen los distintos cambios que se producen. Desarrollo: Se revisan los distintos modelos experimentales que pueden ser utilizados en la investigación en la esclerosis múltiple, tanto in vitro como in vivo. En relación a los modelos in vitro se analizan los distintos cultivos celulares y sus potenciales modificaciones así como los modelos en rodajas. En los modelos in vivo, se analizan los modelos de base inmune-inflamatoria como la encefalitis alérgica experimental en los distintos animales, además de las enfermedades desmielinizantes por virus. Por otro lado, se analizan los modelos de desmielinización-remielinización incluyéndose las lesiones químicas por cuprizona, lisolecitina, bromuro de etidio, así como el modelo de zebrafish y los modelos transgénicos. Conclusiones: Los modelos experimentales nos permiten acercarnos al conocimiento de los diversos mecanismos que ocurren en la esclerosis múltiple. La utilización de cada uno de ellos depende de los objetivos de investigación que planteen. Abstract: Introduction: Experimental animal models constitute a useful tool to deepen our knowledge of central nervous system disorders. In the case of multiple sclerosis, however, there is no such specific model able to provide an overview of the disease; multiple models covering the different pathophysiological features of the disease are therefore necessary. Development: We reviewed the different in vitro and in vivo experimental models used in multiple sclerosis research. Concerning in vitro models, we analysed cell cultures and slice models. As for in vivo models, we examined such models of autoimmunity and inflammation as experimental allergic encephalitis in different animals and virus-induced demyelinating diseases. Furthermore, we analysed models of demyelination and remyelination, including chemical lesions caused by cuprizone, lysolecithin, and ethidium bromide; zebrafish; and transgenic models. Conclusions: Experimental models provide a deeper understanding of the different pathogenic mechanisms involved in multiple sclerosis. Choosing one model or another depends on the specific aims of the study. Palabras clave: Modelos experimentales, Desmielinización, Remielinización, Esclerosis múltiple, Encefalitis alérgica experimental, Mielina, Keywords: Experimental models, Demyelination, Remyelination, Multiple sclerosis, Experimental allergic encephalitis, Myelin

Background: Primary progressive aphasia (PPA) is a heterogeneous syndrome that is difficult to diagnose at early stages. Plasma neurofilament light chain (NFL) has been proposed as a potential biomarker for PPA. Objective: To examine the diagnostic properties of plasma NFL in PPA and to evaluate its association with clinical stages of the disease and brain metabolism. Methods: Our study included 80 participants (13 with non-fluent, 12 with semantic, and 16 with logopenic variant PPA; 13 with amnestic Alzheimer's disease [AD]; 13 with behavioral variant frontotemporal dementia; and 13 healthy controls). Plasma NFL concentration was measured using a high-sensitivity enzyme-linked immunosorbent assay (ELISA) kit. PET imaging was performed in a subgroup of patients. Results: NFL discriminated patients from controls with an area under the curve of 0.914 (95% CI, 0.843-0.984; p

We aimed to study the expression of circulating heat-shock protein HSP70 and exosomes in plasma of a cohort of patients with Alzheimer's disease (AD) and frontotemporal dementia (FTD) at different stages. We performed correlations with clinical scales and FDG-PET. HSP70 levels were higher within exosomes than free in plasma. Moderate correlations were found between exosomal HSP70 and CDR, FTLD-CDR, and extension of hypometabolism. Our results suggest modifications in the level of exosomal HSP70 during the course of neurodegeneration, regardless of AD or FTD, and therefore HSP70 could have a potential role in the follow-up of these disorders.

Introduction Culturally fair cognitive assessments sensitive to detecting changes associated with prodromal Alzheimer's disease are needed. Methods Performance of Hispanic and non-Hispanic older adults on the Loewenstein-Acevedo Scale of Semantic Interference and Learning (LASSI-L) was examined in persons with amnestic mild cognitive impairment (aMCI) or normal cognition. The association between a novel cognitive marker, the failure to recover from proactive semantic interference (frPSI), and cortical thinning was explored. Results English-speaking aMCI participants scored lower than cognitively normal participants on all LASSI-L indices, while Spanish-speaking aMCI participants scored lower in learning, frPSI, and delayed recall. Healthy controls obtained equivalent scores on all indices except retroactive semantic interference. English-speaking and Spanish-speaking aMCI participants had equivalent scores except English speaker's greater vulnerability to frPSI. Across aMCI groups, frPSI was associated with cortical thinning of the entorhinal cortex and precuneus (r = −0.45 to r = 0.52; P, Highlights • Culturally fair outcome measures sensitive to detecting prodromal Alzheimer's disease are needed. • The Loewenstein-Acevedo Scale of Semantic Interference and Learning differentiates amnestic mild cognitive impairment from cognitively normal Hispanic elderly, a growing minority group. • A sensitive marker, failure to recover from proactive semantic interference, was implicated in amnestic mild cognitive impairment, regardless of culture/language. • The failure to recover from proactive semantic interference was associated with cortical thinning in Alzheimer's disease–prone regions.

Background. Primary progressive aphasia (PPA) is a neurodegenerative syndrome in which diagnosis is usually challenging. Biomarkers are needed for diagnosis and monitoring. In this study, we aimed to evaluate Electroencephalography (EEG) as a biomarker for the diagnosis of PPA. Methods. We conducted a cross-sectional study with 40 PPA patients categorized as non-fluent, semantic, and logopenic variants, and 20 controls. Resting-state EEG with 32 channels was acquired and preprocessed using several procedures (quantitative EEG, wavelet transformation, autoencoders, and graph theory analysis). Seven machine learning algorithms were evaluated (Decision Tree, Elastic Net, Support Vector Machines, Random Forest, K-Nearest Neighbors, Gaussian Naive Bayes, and Multinomial Naive Bayes). Results. Diagnostic capacity to distinguish between PPA and controls was high (accuracy 75%, F1-score 83% for kNN algorithm). The most important features in the classification were derived from network analysis based on graph theory. Conversely, discrimination between PPA variants was lower (Accuracy 58% and F1-score 60% for kNN). Conclusions. The application of ML to resting-state EEG may have a role in the diagnosis of PPA, especially in the differentiation from controls. Future studies with high-density EEG should explore the capacity to distinguish between PPA variants.

Background: Primary progressive aphasia (PPA) is a neurodegenerative syndrome with three main clinical variants: non-fluent, semantic, and logopenic. Clinical diagnosis and accurate classification are challenging and often time-consuming. The Mini-Linguistic State Examination (MLSE) has been recently developed as a short language test to specifically assess language in neurodegenerative disorders. Objective: Our aim was to adapt and validate the Spanish version of MLSE for PPA diagnosis. Methods: Cross-sectional study involving 70 patients with PPA and 42 healthy controls evaluated with the MLSE. Patients were independently diagnosed and classified according to comprehensive cognitive evaluation and advanced neuroimaging. Results: Internal consistency was 0.758. The influence of age and education was very low. The area under the curve for discriminating PPA patients and healthy controls was 0.99. Effect sizes were moderate-large for the discrimination between PPA and healthy controls. Motor speech, phonology, and semantic subscores discriminated between the three clinical variants. A random forest classification model obtained an F1-score of 81%for the three PPA variants. Conclusion: Our study provides a brief and useful language test for PPA diagnosis, with excellent properties for both clinical routine assessment and research purposes.

Background Primary progressive aphasia (PPA) is a clinical syndrome characterized by gradual loss of language skills. This study aimed to evaluate the diagnostic capacity of a connected speech task for the diagnosis of PPA and its variants, to determine the main components of spontaneous speech, and to examine their neural correlates. Methods A total of 118 (31 patients with nfvPPA, 11 with svPPA, 45 with lvPPA, and 31 healthy controls) were evaluated with the Cookie Theft picture description task and a comprehensive language assessment protocol. Patients also underwent 18F-fluorodeoxyglucose positron emission tomography and magnetic resonance imaging studies. Principal component analysis and machine learning were used to evaluate the main components of connected speech and the accuracy of connected speech parameters for diagnosing PPA. Voxel-based analyses were conducted to evaluate the correlation between spontaneous speech components and brain metabolism, brain volumes, and white matter microstructure. Results Discrimination between patients with PPA and controls was 91.67%, with 77.78% discrimination between PPA variants. Parameters related to speech rate and lexical variables were the most discriminative for classification. Three main components were identified: lexical features, fluency, and syntax. The lexical component was associated with ventrolateral frontal regions, while the fluency component was associated with the medial superior prefrontal cortex. Number of pauses was more related with the left parietotemporal region, while pauses duration with the bilateral frontal lobe. The lexical component was correlated with several tracts in the language network (left frontal aslant tract, left superior longitudinal fasciculus I, II, and III, left arcuate fasciculus, and left uncinate fasciculus), and fluency was linked to the frontal aslant tract. Conclusion Spontaneous speech assessment is a useful, brief approach for the diagnosis of PPA and its variants. Neuroimaging correlates suggested a subspecialization within the left frontal lobe, with ventrolateral regions being more associated with lexical production and the medial superior prefrontal cortex with speech rate.

Introduction: AQP4 (aquaporin-4)–immunoglobulin G (IgG)-mediated neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory demyelinating disease that affects the central nervous system, particularly the spinal cord and optic nerve, remyelination capacity in neuromyelitis optica is yet to be determined, as is the role of AQP4–IgG in cell differentiation. Material and Methods: We included three groups—a group of patients with AQP4–IgG-positive neuromyelitis optica, a healthy group, and a sham group. We analyzed differentiation capacity in cultures of neurospheres from the subventricular zone of mice by adding serum at two different times: early and advanced stages of differentiation. We also analyzed differentiation into different cell lines. Results and Conclusions: The effect of sera from patients with NMOSD on precursor cells differs according to the degree of differentiation, and probably affects oligodendrocyte progenitor cells from NG2 cells to a lesser extent than cells from the subventricular zone, however, the resulting oligodendrocytes may be compromised in terms of maturation and possibly limited in their ability to generate myelin. Furthermore, these cells decrease in number with age. It is very unlikely that the use of drugs favoring the migration and differentiation of oligodendrocyte progenitor cells in multiple sclerosis would be effective in the context of neuromyelitis optica, but cell therapy with oligodendrocyte progenitor cells seems to be a potential alternative.

The cognitive and language processes underlying verbal fluency remain unclear. While some cognitive processes related to memory and executive functioning have been more associated with category and letter verbal fluency, other less studied aspects of language ability could be also related. We discuss the contribution of the recent study by Lebkuecher and colleagues (2021) about the role of language in verbal fluency, and the data from other studies evaluating the cognitive and neuroimaging correlates of verbal fluency in MS.

Primary progressive aphasia (PPA) is mainly considered a sporadic disease and few studies have systematically analyzed its genetic basis. We here report the analyses of C9orf72 genotyping and whole-exome sequencing data in a consecutive and well-characterized cohort of 50 patients with PPA. We identified three pathogenic GRN variants, one of them unreported, and two cases with C9orf72 expansions. In addition, one likely pathogenic variant was found in the SQSTM1 gene. Overall, we found 12%of patients carrying pathogenic or likely pathogenic variants. These results support the genetic role in the pathophysiology of a proportion of patients with PPA.

The goal of developing a PET dedicated to the brain (CareMiBrain) has evolved from its initial approach to diagnosis and monitoring of dementias, to the more ambitious of creating a revolutionary clinical pathway for the knowledge and personalized treatment of multiple neurological diseases. The main innovative feature of CareMiBrain is the use of detectors with continuous crystals, which allow a high resolution determination of the depth of annihilation photons interaction within the thickness of the scintillation crystal. The technical validation phase of the equipment consisted of a pilot, prospective and observational study whose objective was to obtain the first images (40 patients), analyze them and make adjustments in the acquisition, reconstruction and correction parameters, comparing the image quality of the CareMiBrain equipment with that of the whole-body PET-CT. Thanks to the team meetings and the joint analysis of the images, it was possible to detect its weak points and some of its causes. The calibration, acquisition and processing processes, as well as the reconstruction, were optimized, the number of iterations was set to achieve the best signal-to-noise ratio, the random correction was optimized and a post-processing algorithm was included in the reconstruction algorithm. The main technical improvements implemented in this phase of technical validation carried out through collaboration of the Services of Nuclear Medicine and Neurology of the Hospital Clinico San Carlos with the Spanish company Oncovision will be exposed in a project financed with funds from the European Union (Horizon 2020 innovation program, 713323).

The Five-Point Test (5PT) is a neuropsychological tool for examining design or figural fluency. In this study, we aimed to provide normative data for the 5PT in Spain. Also, we aimed to compare the norms collected in our research with other normative studies from other populations to evaluate a potential cross-cultural application of 5PT. One hundred and ninety-two healthy subjects aged were enrolled. The mean age was 68.48 ± 9.68 years old (range 50-89), and mean years of education were 10.65 ± 5.22. There were 117 (60.9%) women. The overlapping interval strategy was used to maximize the sample size. Age- and education-adjusted scores were estimated using linear regression analysis. Intraclass correlation coefficient was used to calculate agreement with norms from other countries. Age and years of formal education showed moderate correlations with the scores, while the influence of sex was non-significant. Intraclass correlation coefficient (absolute agreement) between Spanish and German norms was 0.956 (95% confidence interval 0.906-0.978). Norms for unique designs at 1, 2, and 3 minutes are provided. Our study confirms the influence of age and education on design fluency and provides normative data for people older than 50 years old. We hypothesize that 5PT might be a useful test in cross-cultural settings.

BackgroundPause duration analysis is a common feature in the study of discourse in Alzheimer’s disease (AD) and may also be helpful for its early detection. However, studies involving patients with amnestic mild cognitive impairment (aMCI) have yielded varying results.ObjectivesTo characterize the probability density distribution of speech pause durations in AD, two multi-domain amnestic MCI patients (with memory encoding deficits, a-mdMCI-E, and with retrieval impairment only, a-mdMCI-R) and healthy controls (HC) in order check whether there are significant differences between them.Method112 picture-based oral narratives were manually transcribed and annotated for the automatic extraction and analysis of pause durations. Different probability distributions were tested for the fitting of pause durations while truncating shorter ranges. Recent findings in the field of Statistics were considered in order to avoid the inherent methodological uncertainty that this type of analysis entails.ResultsA lognormal distribution (LND) explained the distribution of pause duration for all groups. Its fitted parameters (µ,σ) followed a gradation from the group with shorter durations and a higher tendency to produce short pauses (HC) to the group with longer pause durations and a considerably higher tendency to produce long pauses with greater variance (AD). Importantly, a-mdMCI-E produced significantly longer pauses and with greater variability than their a-mdMCI-R counterparts (α= 0.05).ConclusionWe report significant differences at the group level in pause distribution across all groups of study that could be used in future diagnostic tools and discuss the clinical implications of these findings, particularly regarding the characterization of aMCI.

Background: Verbal fluency (VF) has been associated with several cognitive functions, but the cognitive processes underlying verbal fluency deficits in Multiple Sclerosis (MS) are controversial. Further knowledge about VF could be useful in clinical practice, because these tasks are brief, applicable, and reliable in MS patients. In this study, we aimed to evaluate the cognitive processes related to VF and to develop machine-learning algorithms to predict those patients with cognitive deficits using only VF-derived scores.Methods: Two hundred participants with MS were enrolled and examined using a comprehensive neuropsychological battery, including semantic and phonemic fluencies. Automatic linear modeling was used to identify the neuropsychological test predictors of VF scores. Furthermore, machine-learning algorithms (support vector machines, random forest) were developed to predict those patients with cognitive deficits using only VF-derived scores.Results: Neuropsychological tests associated with attention-executive functioning, memory, and language were the main predictors of the different fluency scores. However, the importance of memory was greater in semantic fluency and clustering scores, and executive functioning in phonemic fluency and switching. Machine learning algorithms predicted general cognitive impairment and executive dysfunction, with F1-scores over 67–71%.Conclusions: VF was influenced by many other cognitive processes, mainly including attention-executive functioning, episodic memory, and language. Semantic fluency and clustering were more explained by memory function, while phonemic fluency and switching were more related to executive functioning. Our study supports that the multiple cognitive components underlying VF tasks in MS could serve for screening purposes and the detection of executive dysfunction.

Objectives The assessment of social cognition changes may be challenging, especially in the earliest stages of some neurodegenerative diseases. Our objective was to validate a social cognition battery from a multidomain perspective. In this regard, we aimed to adapt several tests, collect normative data, and validate them in prodromal Alzheimer’s disease (AD) and multiple sclerosis (MS). Methods A total of 92 healthy controls, 25 prodromal AD, and 39 MS patients were enrolled. Age-, gender-, and education-matched control groups were created for comparisons. Social cognition battery was composed of an emotion-labeling task developed from FACES database, the Story-based Empathy test (SET), the Faux Pas test, and the Interpersonal Reactivity Index. Patients were also evaluated with a comprehensive cognitive battery to evaluate the other cognitive domains. Automatic linear modeling was used to predict each social cognition test’s performance using the neuropsychological tests examining other cognitive domains. Results The reliability of the battery was moderate-high. Significant intergroup differences were found with medium-large effect sizes. Moderate correlations were found between social cognition battery and neuropsychological tests. The emotion labeling task and SET showed moderate correlations with age and education, and age, respectively. Regression-based norms were created considering the relevant demographic variables. Linear regression models including other neuropsychological tests explained between 7.7% and 68.8% of the variance of the social cognition tests performance. Conclusions Our study provides a battery for the assessment of social cognition in prodromal AD and MS with Spanish normative data to improve the evaluation in clinical and research settings.