RESUMEN
Neuroinflammation is a hallmark of Alzheimer's disease (AD) and both positive and negative associations of individual inflammation-related markers with brain structure and cognitive function have been described. We aimed to identify inflammatory signatures of CSF immune-related markers that relate to changes of brain structure and cognition across the clinical spectrum ranging from normal aging to AD. A panel of 16 inflammatory markers, Aß42/40 and p-tau181 were measured in CSF at baseline in the DZNE DELCODE cohort (n = 295); a longitudinal observational study focusing on at-risk stages of AD. Volumetric maps of gray and white matter (GM/WM; n = 261) and white matter hyperintensities (WMHs, n = 249) were derived from baseline MRIs. Cognitive decline (n = 204) and the rate of change in GM volume was measured in subjects with at least 3 visits (n = 175). A principal component analysis on the CSF markers revealed four inflammatory components (PCs). Of these, the first component PC1 (highly loading on sTyro3, sAXL, sTREM2, YKL-40, and C1q) was associated with older age and higher p-tau levels, but with less pathological Aß when controlling for p-tau. PC2 (highly loading on CRP, IL-18, complement factor F/H and C4) was related to male gender, higher body mass index and greater vascular risk. PC1 levels, adjusted for AD markers, were related to higher GM and WM volumes, less WMHs, better baseline memory, and to slower atrophy rates in AD-related areas and less cognitive decline. In contrast, PC2 related to less GM and WM volumes and worse memory at baseline. Similar inflammatory signatures and associations were identified in the independent F.ACE cohort. Our data suggest that there are beneficial and detrimental signatures of inflammatory CSF biomarkers. While higher levels of TAM receptors (sTyro/sAXL) or sTREM2 might reflect a protective glia response to degeneration related to phagocytic clearance, other markers might rather reflect proinflammatory states that have detrimental impact on brain integrity.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides , Biomarcadores , Encéfalo , Cognición , Disfunción Cognitiva , Inflamación , Imagen por Resonancia Magnética , Sustancia Blanca , Proteínas tau , Humanos , Masculino , Femenino , Biomarcadores/líquido cefalorraquídeo , Anciano , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/patología , Persona de Mediana Edad , Encéfalo/patología , Péptidos beta-Amiloides/líquido cefalorraquídeo , Cognición/fisiología , Inflamación/líquido cefalorraquídeo , Imagen por Resonancia Magnética/métodos , Disfunción Cognitiva/líquido cefalorraquídeo , Sustancia Blanca/patología , Proteínas tau/líquido cefalorraquídeo , Estudios Longitudinales , Sustancia Gris/patología , Estudios de CohortesRESUMEN
Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease characterized by the loss of motor control. Current understanding of ALS pathology is largely based on post-mortem investigations at advanced disease stages. A systematic in vivo description of the microstructural changes that characterize early stage ALS, and their subsequent development, is so far lacking. Recent advances in ultra-high field (7â T) MRI data modelling allow us to investigate cortical layers in vivo. Given the layer-specific and topographic signature of ALS pathology, we combined submillimetre structural 7 T MRI data (qT1, QSM), functional localizers of body parts (upper limb, lower limb, face) and layer modelling to systematically describe pathology in the primary motor cortex (M1), in 12 living ALS patients with reference to 12 matched controls. Longitudinal sampling was performed for a subset of patients. We calculated multimodal pathology maps for each layer (superficial layer, layer 5a, layer 5b, layer 6) of M1 to identify hot spots of demyelination, iron and calcium accumulation in different cortical fields. We show preserved mean cortical thickness and layer architecture of M1, despite significantly increased iron in layer 6 and significantly increased calcium in layer 5a and superficial layer, in patients compared to controls. The behaviourally first-affected cortical field shows significantly increased iron in L6 compared to other fields, while calcium accumulation is atopographic and significantly increased in the low myelin borders between cortical fields compared to the fields themselves. A subset of patients with longitudinal data shows that the low myelin borders are particularly disrupted and that calcium hot spots, but to a lesser extent iron hot spots, precede demyelination. Finally, we highlight that a very slow progressing patient (Patient P4) shows a distinct pathology profile compared to the other patients. Our data show that layer-specific markers of in vivo pathology can be identified in ALS patients with a single 7â T MRI measurement after first diagnosis, and that such data provide critical insights into the individual disease state. Our data highlight the non-topographic architecture of ALS disease spread and the role of calcium, rather than iron accumulation, in predicting future demyelination. We also highlight a potentially important role of low myelin borders, that are known to connect to multiple areas within the M1 architecture, in disease spread. Finally, the distinct pathology profile of a very-slow progressing patient (Patient P4) highlights a distinction between disease duration and progression. Our findings demonstrate the importance of in vivo histology imaging for the diagnosis and prognosis of neurodegenerative diseases such as ALS.
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Esclerosis Amiotrófica Lateral , Enfermedades Desmielinizantes , Dermatitis , Enfermedades Neurodegenerativas , Humanos , Calcio , Esclerosis Amiotrófica Lateral/diagnóstico por imagen , HierroRESUMEN
The neurotrophic growth factor brain-derived neurotrophic factor (BDNF) plays a crucial role in various neurodegenerative and psychiatric diseases, such as Alzheimer's disease, schizophrenia and depression. BDNF has been proposed as a potential biomarker for diagnosis, prognosis and monitoring therapy. Understanding the factors influencing BDNF levels and whether they follow a circadian rhythm is essential for interpreting fluctuations in BDNF measurements. We aimed to investigate the circadian rhythm of BDNF by collecting multiple peripheral venous blood samples from young, healthy male participants at 12 different time points over 24 h. In addition, vital parameters, cortisol and insulin like growth factor 1 (IGF1) were measured to explore potential regulatory mechanisms, interfering variables and their correlations with BDNF concentration. The findings revealed that plasma BDNF did not exhibit any significant fluctuations over 24 h, suggesting the absence of a circadian rhythm. However, serum BDNF levels decreased during sleep. Furthermore, serum BDNF showed a positive correlation with heart rate but a negative correlation with IGF1. No significant correlation was observed between cortisol and BDNF or IGF1. Although plasma BDNF suggests steady-state conditions, the decline of serum BDNF during the nocturnal period could be attributed to physical inactivity and associated with reduced haemodynamic blood flow (heart rate reduction during sleep). The type of sample collection (peripheral venous cannula vs. blood sampling using a butterfly system) does not significantly affect the measured BDNF levels. The sample collection during the day did not significantly affect BDNF analysis, emphasizing the importance of considering activity levels rather than timing when designing standardized protocols for BDNF assessments.
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Brain-derived neurotrophic factor (BDNF) is a crucial mediator of neuronal plasticity. Here, we investigated the effects of controlled normobaric hypoxia (NH) combined with physical inactivity on BDNF blood levels and executive functions. A total of 25 healthy adults (25.8 ± 3.3 years, 15 female) were analyzed in a randomized controlled cross-over study. Each intervention began with a 30 min resting phase under normoxia (NOR), followed by a 90 min continuation of NOR or NH (peripheral oxygen saturation [SpO2] 85-80%). Serum and plasma samples were collected every 15 min. Heart rate and SpO2 were continuously measured. Before and after each exposure, cognitive tests were performed and after 24 h another follow-up blood sample was taken. NH decreased SpO2 (p < 0.001, ηp2 = 0.747) and increased heart rate (p = 0.006, ηp2 = 0.116) significantly. The 30-min resting phase under NOR led to a significant BDNF reduction in serum (p < 0.001, ηp2 = 0.581) and plasma (p < 0.001, ηp2 = 0.362). Continuation of NOR further significantly reduced BDNF after another 45 min (p = 0.018) in serum and after 30 min (p = 0.040) and 90 min (p = 0.005) in plasma. There was no significant BDNF decline under NH. A 24 h follow-up examination showed a significant decline in serum BDNF, both after NH and NOR. Our results show that NH has the potential to counteract physical inactivity-induced BDNF decline. Therefore, our study emphasizes the need for a physically active lifestyle and its positive effects on BDNF. This study also demonstrates the need for a standardized protocol for future studies to determine BDNF in serum and plasma.
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Factor Neurotrófico Derivado del Encéfalo , Frecuencia Cardíaca , Hipoxia , Conducta Sedentaria , Humanos , Factor Neurotrófico Derivado del Encéfalo/sangre , Femenino , Masculino , Adulto , Hipoxia/sangre , Estudios Cruzados , Ejercicio Físico , Adulto JovenRESUMEN
The primary somatosensory cortex (SI) contains fine-grained tactile representations of the body, arranged in an orderly fashion. The use of ultra-high resolution fMRI data to detect group differences, for example between younger and older adults' SI maps, is challenging, because group alignment often does not preserve the high spatial detail of the data. Here, we use robust-shared response modeling (rSRM) that allows group analyses by mapping individual stimulus-driven responses to a lower dimensional shared feature space, to detect age-related differences in tactile representations between younger and older adults using 7T-fMRI data. Using this method, we show that finger representations are more precise in Brodmann-Area (BA) 3b and BA1 compared to BA2 and motor areas, and that this hierarchical processing is preserved across age groups. By combining rSRM with column-based decoding (C-SRM), we further show that the number of columns that optimally describes finger maps in SI is higher in younger compared to older adults in BA1, indicating a greater columnar size in older adults' SI. Taken together, we conclude that rSRM is suitable for finding fine-grained group differences in ultra-high resolution fMRI data, and we provide first evidence that the columnar architecture in SI changes with increasing age.
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Mapeo Encefálico , Corteza Somatosensorial , Humanos , Anciano , Mapeo Encefálico/métodos , Corteza Somatosensorial/diagnóstico por imagen , Corteza Somatosensorial/fisiología , Dedos/fisiología , Imagen por Resonancia Magnética/métodos , Tacto/fisiologíaRESUMEN
The association between cerebral blood supply and cognition has been widely discussed in the recent literature. One focus of this discussion has been the anatomical variability of the circle of Willis, with morphological differences being present in more than half of the general population. While previous studies have attempted to classify these differences and explore their contribution to hippocampal blood supply and cognition, results have been controversial. To disentangle these previously inconsistent findings, we introduce Vessel Distance Mapping (VDM) as a novel methodology for evaluating blood supply, which allows for obtaining vessel pattern metrics with respect to the surrounding structures, extending the previously established binary classification into a continuous spectrum. To accomplish this, we manually segmented hippocampal vessels obtained from high-resolution 7T time-of-flight MR angiographic imaging in older adults with and without cerebral small vessel disease, generating vessel distance maps by computing the distances of each voxel to its nearest vessel. Greater values of VDM-metrics, which reflected higher vessel distances, were associated with poorer cognitive outcomes in subjects affected by vascular pathology, while this relation was not observed in healthy controls. Therefore, a mixed contribution of vessel pattern and vessel density is proposed to confer cognitive resilience, consistent with previous research findings. In conclusion, VDM provides a novel platform, based on a statistically robust and quantitative method of vascular mapping, for addressing a variety of clinical research questions.
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Enfermedades de los Pequeños Vasos Cerebrales , Imagen por Resonancia Magnética , Humanos , Anciano , Imagen por Resonancia Magnética/métodos , Cognición , Enfermedades de los Pequeños Vasos Cerebrales/patología , Hipocampo/patologíaRESUMEN
The brain's extracellular matrix (ECM) is assumed to undergo rearrangements in Alzheimer's disease (AD). Here, we investigated changes of key components of the hyaluronan-based ECM in independent samples of post-mortem brains (N = 19), cerebrospinal fluids (CSF; N = 70), and RNAseq data (N = 107; from The Aging, Dementia and TBI Study) of AD patients and non-demented controls. Group comparisons and correlation analyses of major ECM components in soluble and synaptosomal fractions from frontal, temporal cortex, and hippocampus of control, low-grade, and high-grade AD brains revealed a reduction in brevican in temporal cortex soluble and frontal cortex synaptosomal fractions in AD. In contrast, neurocan, aggrecan and the link protein HAPLN1 were up-regulated in soluble cortical fractions. In comparison, RNAseq data showed no correlation between aggrecan and brevican expression levels and Braak or CERAD stages, but for hippocampal expression of HAPLN1, neurocan and the brevican-interaction partner tenascin-R negative correlations with Braak stages were detected. CSF levels of brevican and neurocan in patients positively correlated with age, total tau, p-Tau, neurofilament-L and Aß1-40. Negative correlations were detected with the Aß ratio and the IgG index. Altogether, our study reveals spatially segregated molecular rearrangements of the ECM in AD brains at RNA or protein levels, which may contribute to the pathogenic process.
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Enfermedad de Alzheimer , Neurocano , Humanos , Brevicano/metabolismo , Agrecanos/metabolismo , Neurocano/líquido cefalorraquídeo , Enfermedad de Alzheimer/metabolismo , Matriz Extracelular/metabolismo , Encéfalo/metabolismo , Proteínas tau/metabolismo , Péptidos beta-Amiloides/metabolismo , Biomarcadores/metabolismoRESUMEN
Sporadic cerebral small vessel disease determines age- and vascular-risk-factor-related processes of the small brain vasculature. The underlying pathology develops in a stage-dependent manner - probably over decades - often already starting in midlife. Endothelial and pericyte activation precedes blood-brain barrier leaks, extracellular matrix remodeling and neuroinflammation, which ultimately result in bleeds, synaptic and neural dysfunction. Hemodynamic compromise of the small vessel walls promotes perivascular drainage failure and accumulation of neurotoxic waste products in the brain. Clinical diagnosis is mainly based on magnetic resonance imaging according to the Standards for Reporting Vascular Changes on Neuroimaging 2. Cerebral amyloid angiopathy is particularly stratified according to the Boston v2.0 criteria. Small vessel disease of the brain could be clinically silent, or manifested through a heterogeneous spectrum of diseases, where cognitive decline and stroke-related symptoms are the most common ones. Prevention and therapy are centered around vascular risk factor control, physically and cognitively enriched life style and, presumably, maintenance of a good sleep quality, which promotes sufficient perivascular drainage. Prevention of ischemic stroke through anticoagulation that carries at the same time an increased risk for large brain hemorrhages - particularly in the presence of disseminated cortical superficial siderosis - remains one of the main challenges. The cerebral small vessel disease field is rapidly evolving, focusing on the establishment of early disease stage imaging and biofluid biomarkers of neurovascular unit remodeling and the compromise of perivascular drainage. New prevention and therapy strategies will correspondingly center around the dedicated targeting of, e. g., cellular small vessel wall and perivascular tissue structures. Growing knowledge about brain microvasculature bridging neuroimmunological, neurovascular and neurodegenerative fields might lead to a rethink about apparently separate disease entities and the development of overarching concepts for a common line of prevention and treatment for several diseases.
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Angiopatía Amiloide Cerebral , Enfermedades de los Pequeños Vasos Cerebrales , Humanos , Encéfalo/diagnóstico por imagen , Neuroimagen/métodos , Imagen por Resonancia Magnética/métodos , Enfermedades de los Pequeños Vasos Cerebrales/terapia , Hemorragia CerebralRESUMEN
Background and Objectives: Ultrasound (US) is a non-invasive tool for the in vivo detection of peripheral nerve alterations. Materials and Methods: In this study, we applied nerve US to assist the discrimination between the spectrum of amyotrophic lateral sclerosis (ALS, n = 11), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP, n = 5), and genetically confirmed Charcot-Marie-Tooth disease (CMT, n = 5). All participants and n = 15 controls without neurological diseases underwent high-resolution US of the bilateral tibial nerve. The nerve cross-sectional area (CSA) and nerve microvascular blood flow were compared between the groups and related to cerebrospinal fluid (CSF) measures, clinical symptoms, and nerve conduction studies. The analyses are part of a larger multimodal study on the comparison between US and 7 Tesla (7T) magnetic resonance neurography (MRN). Results: The patients and controls were matched with respect to their demographical data. CMT had the longest disease duration, followed by CIDP and ALS. CSA was related to age, weight, and disease duration. CSA was larger in CMT and CIDP compared to ALS and controls. The blood flow was greatest in CIDP, and higher than in CMT, ALS, and controls. In ALS, greater CSA was correlated with greater CSF total protein and higher albumin quotient. The US measures did not correlate with clinical scores or nerve conduction studies in any of the subgroups. Conclusion: Our results point towards the feasibility of CSA and blood flow to discriminate between ALS, CIDP, and CMT, even in groups of small sample size. In ALS, larger CSA could indicate an inflammatory disease subtype characterized by reduced blood-nerve barrier integrity. Our upcoming analysis will focus on the additive value of 7T MRN in combination with US to disentangle the spectrum between more inflammatory or more degenerative disease variants among the disease groups.
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Esclerosis Amiotrófica Lateral , Polineuropatías , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante , Humanos , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/diagnóstico por imagen , Esclerosis Amiotrófica Lateral/diagnóstico por imagen , Nervios Periféricos/diagnóstico por imagen , Polineuropatías/diagnóstico por imagen , Ultrasonografía/métodosRESUMEN
BACKGROUND: Myasthenic crisis (MC) and disease exacerbation in myasthenia gravis (MG) are associated with significant lethality and continue to impose a high disease burden on affected patients. Therefore, we sought to determine potential predictors for MC and exacerbation as well as to identify factors affecting outcome. METHODS: We examined a retrospective, observational cohort study of patients diagnosed with MG between 2000 and 2021 with a mean follow-up of 62.6 months after diagnosis from eight tertiary hospitals in Germany. A multivariate Cox regression model with follow-up duration as the time variable was used to determine independent risk factors for MC and disease exacerbation. RESULTS: 815 patients diagnosed with MG according to national guidelines were included. Disease severity at diagnosis (quantitative MG score or Myasthenia Gravis Foundation of America class), the presence of thymoma and anti-muscle specific tyrosine kinase-antibodies were independent predictors of MC or disease exacerbation. Patients with minimal manifestation status 12 months after diagnosis had a lower risk of MC and disease exacerbation than those without. The timespan between diagnosis and the start of immunosuppressive therapy did not affect risk. Patients with a worse outcome of MC were older, had higher MGFA class before MC and at admission, and had lower vital capacity before and at admission. The number of comorbidities, requirement for intubation, prolonged mechanical ventilation, and MC triggered by infection were associated with worse outcome. No differences between outcomes were observed comparing treatments with IVIG (intravenous immunoglobulin) vs. plasma exchange vs. IVIG together with plasma exchange. CONCLUSIONS: MC and disease exacerbations inflict a substantial burden of disease on MG patients. Disease severity at diagnosis and antibody status predicted the occurrence of MC and disease exacerbation. Intensified monitoring with emphasis on the prevention of infectious complications could be of value to prevent uncontrolled disease in MG patients.
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Inmunoglobulinas Intravenosas , Miastenia Gravis , Progresión de la Enfermedad , Humanos , Inmunoglobulinas Intravenosas/uso terapéutico , Miastenia Gravis/complicaciones , Miastenia Gravis/epidemiología , Miastenia Gravis/terapia , Estudios Retrospectivos , Factores de RiesgoRESUMEN
OBJECTIVE: Myasthenia gravis (MG) is the most common autoimmune disorder affecting the neuromuscular junction. However, evidence shaping treatment decisions, particularly for treatment-refractory cases, is sparse. Both rituximab and eculizumab may be considered as therapeutic options for refractory MG after insufficient symptom control by standard immunosuppressive therapies. METHODS: In this retrospective observational study, we included 57 rituximab-treated and 20 eculizumab-treated patients with MG to compare the efficacy of treatment agents in generalised, therapy-refractory anti-acetylcholine receptor antibody (anti-AChR-ab)-mediated MG with an observation period of 24 months. Change in the quantitative myasthenia gravis (QMG) score was defined as the primary outcome parameter. Differences between groups were determined in an optimal full propensity score matching model. RESULTS: Both groups were comparable in terms of clinical and demographic characteristics. Eculizumab was associated with a better outcome compared with rituximab, as measured by the change of the QMG score at 12 and 24 months of treatment. Minimal manifestation of disease was more frequently achieved in eculizumab-treated patients than rituximab-treated patients at 12 and 24 months after baseline. However, the risk of myasthenic crisis (MC) was not ameliorated in either group. INTERPRETATION: This retrospective, observational study provides the first real-world evidence supporting the use of eculizumab for the treatment of refractory, anti-AChR-ab positive MG. Nonetheless, the risk of MC remained high and prompts the need for intensified monitoring and further research effort aimed at this vulnerable patient cohort.
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Anticuerpos Monoclonales Humanizados , Miastenia Gravis , Anticuerpos Monoclonales Humanizados/uso terapéutico , Humanos , Estudios Retrospectivos , Rituximab/uso terapéuticoRESUMEN
OBJECTIVE: To assess the incidence of post-operative non-ischaemic cerebral complications as a pivotal outcome parameter with respect to size of cerebral infarction, timing of surgery, and peri-operative management in patients with symptomatic carotid stenosis who underwent carotid endarterectomy (CEA). METHODS: Retrospective analysis of prospectively collected single centre CEA registry data. Consecutive patients with symptomatic carotid stenosis were subjected to standard patch endarterectomy. Brain infarct size was measured from the axial slice of pre-operative computed tomography/magnetic resonance imaging demonstrating the largest infarct dimension and was categorised as large (> 4 cm2), small (≤ 4 cm2), or absent. CEA was performed early (within 14 days) or delayed (15 - 180 days) after the ischaemic event. Peri-operative antiplatelet regimen (none, single, dual) and mean arterial blood pressure during surgery and at post-operative stroke unit monitoring were registered. Non-ischaemic post-operative cerebral complications were recorded comprising haemorrhagic stroke and encephalopathy, i.e., prolonged unconsciousness, delirium, epileptic seizure, or headache. RESULTS: 646 symptomatic patients were enrolled of whom 340 (52.6%) underwent early CEA; 367 patients (56.8%) demonstrated brain infarction corresponding to stenosis induced symptoms which was small in 266 (41.2%) and large in 101 (15.6%). Post-operative non-ischaemic cerebral complications occurred in 12 patients (1.9%; 10 encephalopathies, two haemorrhagic strokes) and were independently associated with large infarcts (adjusted odds ratio [OR] 6.839; 95% confidence interval [CI] 1.699 - 27.534) and median intra-operative mean arterial blood pressure in the upper quartile, i.e., above 120 mmHg (adjusted OR 13.318; 95% CI 2.749 - 64.519). Timing of CEA after the ischaemic event, pre-operative antiplatelet regimen, and post-operative blood pressure were not associated with non-ischaemic cerebral complications. CONCLUSION: Infarct size and unintended high peri-operative blood pressure may increase the risk of non-ischaemic complications at CEA independently of whether performed early or delayed.
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Infarto Encefálico/epidemiología , Estenosis Carotídea/cirugía , Endarterectomía Carotidea/efectos adversos , Complicaciones Posoperatorias/epidemiología , Tiempo de Tratamiento/estadística & datos numéricos , Anciano , Encéfalo/diagnóstico por imagen , Infarto Encefálico/diagnóstico , Infarto Encefálico/etiología , Infarto Encefálico/cirugía , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Atención Perioperativa/métodos , Atención Perioperativa/estadística & datos numéricos , Complicaciones Posoperatorias/diagnóstico , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/cirugía , Estudios Prospectivos , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
Decoding natural hand movements is of interest for human-computer interaction and may constitute a helpful tool in the diagnosis of motor diseases and rehabilitation monitoring. However, the accurate measurement of complex hand movements and the decoding of dynamic movement data remains challenging. Here, we introduce two algorithms, one based on support vector machine (SVM) classification combined with dynamic time warping, and the other based on a long short-term memory (LSTM) neural network, which were designed to discriminate small differences in defined sequences of hand movements. We recorded hand movement data from 17 younger and 17 older adults using an exoskeletal data glove while they were performing six different movement tasks. Accuracy rates in decoding the different movement types were similarly high for SVM and LSTM in across-subject classification, but, for within-subject classification, SVM outperformed LSTM. The SVM-based approach, therefore, appears particularly promising for the development of movement decoding tools, in particular if the goal is to generalize across age groups, for example for detecting specific motor disorders or tracking their progress over time.
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Interfaces Cerebro-Computador , Máquina de Vectores de Soporte , Anciano , Algoritmos , Mano , Humanos , Movimiento , Redes Neurales de la ComputaciónRESUMEN
Vascular damage, central nervous system (CNS) injury, seizure or even psychological stress may trigger activation of microglia and infiltration of other immune cells, accompanied by high levels of expression and activity of extracellular proteases, such as matrix metalloproteinases (MMPs), and degradation/remodelling of the perivascular and perineuronal extracellular matrix (ECM). This acute response is followed by the recovery/chronic phase, during which the activation of astrocytes leads to the upregulated synthesis of ECM molecules, which, in combination with elevated expression of tissue inhibitor of metalloproteinases (TIMP) proteins, increases the aggregation of ECM molecules. This biphasic dysregulation of local balance between extracellular proteases and the ECM activates multiple temporally overlapping signalling cascades, involving receptor-type protein tyrosine phosphatases, integrins, Toll-like receptors, cell adhesion molecules, and ion channels, resulting in impaired synaptic plasticity and cognition. An additional level of complexity is related to the leakage of blood plasma proteins, such as fibrinogen, and the diffusion of perivascularly overproduced MMPs, TIMPs and ECM molecules into the CNS parenchyma, leading to diverse effects on neurons and incorporation of these molecules into the interstitial neural ECM. This review aims to outline these complex common mechanisms in stroke, CNS injury, depression, epilepsy, multiple sclerosis and cerebral small vessel disease and to discuss translational strategies to advance the development of new therapies for these neurological and psychiatric diseases.
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Matriz Extracelular , Trastornos Mentales , Enfermedades del Sistema Nervioso , Astrocitos , Humanos , Metaloproteinasas de la Matriz , Neuronas , Inhibidores Tisulares de MetaloproteinasasRESUMEN
Medial temporal lobe dependent cognitive functions are highly vulnerable to hypoxia in the hippocampal region, yet little is known about the relationship between the richness of hippocampal vascular supply and cognition. Hippocampal vascularization patterns have been categorized into a mixed supply from both the posterior cerebral artery and the anterior choroidal artery or a single supply by the posterior cerebral artery only. Hippocampal arteries are small and affected by pathological changes when cerebral small vessel disease is present. We hypothesized, that hippocampal vascularization patterns may be important trait markers for vascular reserve and modulate (i) cognitive performance; (ii) structural hippocampal integrity; and (iii) the effect of cerebral small vessel disease on cognition. Using high-resolution 7 T time-of-flight angiography we manually classified hippocampal vascularization patterns in older adults with and without cerebral small vessel disease in vivo. The presence of a mixed supplied hippocampus was an advantage in several cognitive domains, including verbal list learning and global cognition. A mixed supplied hippocampus also was an advantage for verbal memory performance in cerebral small vessel disease. Voxel-based morphometry showed higher anterior hippocampal grey matter volume in mixed, compared to single supply. We discuss that a mixed hippocampal supply, as opposed to a single one, may increase the reliability of hippocampal blood supply and thereby provide a hippocampal vascular reserve that protects against cognitive impairment.
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Arterias Cerebrales/patología , Disfunción Cognitiva/fisiopatología , Hipocampo/irrigación sanguínea , Hipocampo/patología , Anciano , Enfermedades de los Pequeños Vasos Cerebrales/complicaciones , Cognición/fisiología , Disfunción Cognitiva/complicaciones , Disfunción Cognitiva/patología , Femenino , Sustancia Gris/irrigación sanguínea , Sustancia Gris/patología , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Memoria/fisiología , Persona de Mediana Edad , Lóbulo Temporal/irrigación sanguínea , Lóbulo Temporal/patologíaRESUMEN
Ultrasound has revealed cross-sectional nerve area (CSA) reduction in amyotrophic lateral sclerosis (ALS), but little is known about the sonographic nerve texture beyond CSA alterations. In a large cohort of 177 ALS patients and 57 control subjects, we investigated the covariance and disease-specific signature of several sonographic texture features of the median and ulnar nerves and their relationship to the patients' clinical characteristics. ALS patients showed atrophic nerves, a loss of the intranerve structures' echoic contrast, elevated coarseness, and a trend toward lower cluster shading compared with controls. A reduction in intranerve echoic contrast was related to longer disease duration and poorer functional status in ALS. Sonographic texture markers point toward a significant reorganization of the deep nerve microstructure in ALS. Future studies will be needed to further substantiate the markers' potential to assess peripheral nerve alterations in ALS.
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Esclerosis Amiotrófica Lateral/diagnóstico por imagen , Esclerosis Amiotrófica Lateral/patología , Nervio Mediano/patología , Nervio Cubital/patología , Ultrasonografía , Anciano , Femenino , Antebrazo/inervación , Humanos , Masculino , Nervio Mediano/diagnóstico por imagen , Persona de Mediana Edad , Nervio Cubital/diagnóstico por imagen , Ingenio y Humor como AsuntoRESUMEN
BACKGROUND: We present one patient with an initial diagnosis of Guillain-Barré syndrome (GBS) and one with Charcot-Marie-Tooth disease (CMT) type 1A. METHODS: Both patients underwent ankle tibial nerve fusion-imaging of high-resolution ultrasound (HRUS) with 7T MR neurography (MRN). RESULTS: In GBS, the nerve was enlarged, T2-hyperintense, and showed increased vascularization 21 months after symptom onset. In CMT1A, the enlarged nerve was T2-isointense with normal endoneurial blood flow. CONCLUSIONS: We demonstrate the utility of 7T-MRN-HRUS-fusion-imaging. In GBS, there was evidence of ongoing inflammation resulting in a changed diagnosis to acute-onset chronic demyelinating polyradiculoneuropathy and maintenance of immunotherapy. By MRN-HRUS-fusion, patients with presumed peripheral axonal degeneration could be shown to display imaging markers associated with peripheral nervous system inflammation. Thus, more accurate identification of a treatable inflammatory component may become possible.
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Imagen por Resonancia Magnética/métodos , Imagen Multimodal/métodos , Nervio Tibial/diagnóstico por imagen , Ultrasonografía/métodos , Enfermedad de Charcot-Marie-Tooth/diagnóstico por imagen , Femenino , Síndrome de Guillain-Barré/diagnóstico por imagen , Humanos , Persona de Mediana Edad , Flujo Sanguíneo Regional/fisiología , Nervio Tibial/irrigación sanguínea , Adulto JovenRESUMEN
Modern neuromuscular electrodiagnosis (EDX) and neuromuscular ultrasound (NMUS) require a universal language for effective communication in clinical practice and research and, in particular, for teaching young colleagues. Therefore, the AANEM and the IFCN have decided to publish a joint glossary as they feel the need for an updated terminology to support educational activities in neuromuscular EDX and NMUS in all parts of the world. In addition NMUS has been rapidly progressing over the last years and is now widely used in the diagnosis of disorders of nerve and muscle in conjunction with EDX. This glossary has been developed by experts in the field of neuromuscular EDX and NMUS on behalf of the AANEM and the IFCN and has been agreed upon by electronic communication between January and November 2019. It is based on the glossaries of the AANEM from 2015 and of the IFCN from 1999. The EDX and NMUS terms and the explanatory illustrations have been updated and supplemented where necessary. The result is a comprehensive glossary of terms covering all fields of neuromuscular EDX and NMUS. It serves as a standard reference for clinical practice, education and research worldwide. HIGHLIGHTS: Optimal terminology in neuromuscular electrodiagnosis and ultrasound has been revisited. A team of international experts have revised and expanded a standardized glossary. This list of terms serves as standard reference for clinical practice, education and research.
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Diccionarios como Asunto , Electrodiagnóstico/clasificación , Enfermedades Neuromusculares/clasificación , Enfermedades Neuromusculares/diagnóstico por imagen , Sociedades Médicas/clasificación , Ultrasonografía/clasificación , Humanos , Estados UnidosRESUMEN
INTRODUCTION: Approximately 1 out of 4 stroke patients suffers ischemic stroke secondary to atrial fibrillation (AF). Although indicated, withholding of anticoagulants for secondary prevention is a widespread phenomenon. OBJECTIVE: We examined the longitudinal change of recommendation and prescription of secondary preventive anticoagulation in AF patients in an acute stroke center setting focusing on the impact of the introduction of direct oral anticoagulants (DOACs) and the change of national stroke prevention guidelines. METHODS: Consecutive patients admitted with an acute cerebrovascular ischemic event underwent regular diagnostic work-up. Pseudonymized clinical data were entered into the institution's stroke registry. In those patients with AF, discharge letters were collected and evaluated for temporal trends and affecting factors of recommended and prescribed antithrombotic secondary medication at the time of discharge from hospital. RESULTS: Of 7,175 patients admitted between January 2009 and December 2018, 1,812 (25.3%) suffered stroke caused by AF. Frequency of patients with recommended anticoagulation increased within the observation period from 66.7 to 95.8% (per year; adjusted odds ratio [OR], 1.309; confidence interval [CI], 1.153-1.486). Independently from this time trend, DOAC approval (adjusted OR, 4.026; CI 1.962-8.265) and guideline change (adjusted OR, 2.184; CI, 1.006-4.743) were associated with an increasing frequency of recommendation for anticoagulation. The rate of patients already receiving recommended anticoagulation for secondary prevention at discharge increased from 42.1 to 62.5%. Introduction of DOACs was not associated with this trend, and guideline change was even associated with decreasing frequency of anticoagulated patients at hospital discharge (adjusted OR, 0.641; CI, 0.414-0.991). Fear of early intracerebral bleeding was the most common reason for withholding anticoagulation (37%) at hospital discharge and stayed stable during the observation period. CONCLUSIONS: Changing national guidelines with discard of contraindications for anticoagulation and the introduction of DOACs led to a broader recommendation of oral anticoagulation. However, both, new guidelines and DOACs, were not found to be associated with an increasing percentage of patients discharged from our hospital already on recommended anticoagulant prevention. This might be explained by the decreasing length of hospital stay during the study period and a missing evidence of early bleeding risk of DOACs in patients with acute brain infarction. Evidence-based data to close this therapeutic gap are needed.