1,857 research outputs found

    Systemic function impairment and neurodegeneration in the general population

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    Dynamic PET-Tau Quantification for Progressive Supranuclear Palsy Diagnosis

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    Treballs Finals de Grau d'Enginyeria BiomĂšdica. Facultat de Medicina i CiĂšncies de la Salut. Universitat de Barcelona. Curs: 2023-2024. Tutor: RaĂșl Tudela ; Director: Aida Niñerola, RaĂșl TudelaTauopathies are neurodegenerative diseases caused by the abnormal accumulation of tau proteins in the brain. One uncommon tauopathy is progressive supranuclear palsy (PSP), whose symptoms often overlap with other brain disorders, and its detection is only possible postmortem since there is not an available ideal biomarker. PET-tau imaging has the potential to revolutionize the early detection of this disease. PET is a nuclear imaging test which allows seeing the functionality of organs and tissues in vivo using a radiotracer that emits radiation from inside the body. A new PET tracer called 18F-PI-2620 has shown promising results concerning the detection of PSP, with high affinity to tau aggregates and low off-target binding. This project consists of designing and testing a software for the quantification of PET images of the brain with a dynamic acquisition, which show the radiotracer distribution through time. The software performs a coregistration of the images to the standard space, where the different regions of the brain can be segmented using an atlas, and provides two physiologically meaningful parameters which are the Distribution Volume Ratio (DVR) and Standardized Uptake Value Ratio (SUVR). It gives out the DVR and SUVR values for any region of interest, as well as parametric images which help visualizing the radiotracer distribution in the brain. A set of brain PET images from 13 subjects acquired using 18F-PI-2620 has been used for the development and testing of the software, divided into healthy controls, subjects with Down syndrome, some of whom have developed Alzheimer’s disease (AD), which also implies a higher amount of abnormal deposited tau proteins. The results have shown higher DVR and SUVR values for several brain regions in those subjects who have developed AD, confirming that they have a higher radiotracer uptake and a greater amount of deposited tau proteins. This proves the correct functionality of the software and its potential as a future tool for detecting tauopathies such as PSP in combination with the radiotracer

    Recommendations for reproducibility of cerebrospinal fluid extracellular vesicle studies

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    Cerebrospinal fluid (CSF) is a clear, transparent fluid derived from blood plasma that protects the brain and spinal cord against mechanical shock, provides buoyancy, clears metabolic waste and transports extracellular components to remote sites in the brain. Given its contact with the brain and the spinal cord, CSF is the most informative biofluid for studies of the central nervous system (CNS). In addition to other components, CSF contains extracellular vesicles (EVs) that carry bioactive cargoes (e.g., lipids, nucleic acids, proteins), and that can have biological functions within and beyond the CNS. Thus, CSF EVs likely serve as both mediators of and contributors to communication in the CNS. Accordingly, their potential as biomarkers for CNS diseases has stimulated much excitement for and attention to CSF EV research. However, studies on CSF EVs present unique challenges relative to EV studies in other biofluids, including the invasive nature of CSF collection, limited CSF volumes and the low numbers of EVs in CSF as compared to plasma. Here, the objectives of the International Society for Extracellular Vesicles CSF Task Force are to promote the reproducibility of CSF EV studies by providing current reporting and best practices, and recommendations and reporting guidelines, for CSF EV studies. To accomplish this, we created and distributed a world‐wide survey to ISEV members to assess methods considered ‘best practices’ for CSF EVs, then performed a detailed literature review for CSF EV publications that was used to curate methods and resources. Based on responses to the survey and curated information from publications, the CSF Task Force herein provides recommendations and reporting guidelines to promote the reproducibility of CSF EV studies in seven domains: (i) CSF Collection, Processing, and Storage; (ii) CSF EV Separation/Concentration; (iii) CSF EV Size and Number Measurements; (iv) CSF EV Protein Studies; (v) CSF EV RNA Studies; (vi) CSF EV Omics Studies and (vii) CSF EV Functional Studies

    A Spark Of Emotion: The Impact of Electrical Facial Muscle Activation on Emotional State and Affective Processing

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    Facial feedback, which involves the brain receiving information about the activation of facial muscles, has the potential to influence our emotional states and judgments. The extent to which this applies is still a matter of debate, particularly considering a failed replication of a seminal study. One factor contributing to the lack of replication in facial feedback effects may be the imprecise manipulation of facial muscle activity in terms of both degree and timing. To overcome these limitations, this thesis proposes a non-invasive method for inducing precise facial muscle contractions, called facial neuromuscular electrical stimulation (fNMES). I begin by presenting a systematic literature review that lays the groundwork for standardising the use of fNMES in psychological research, by evaluating its application in existing studies. This review highlights two issues, the lack of use of fNMES in psychology research and the lack of parameter reporting. I provide practical recommendations for researchers interested in implementing fNMES. Subsequently, I conducted an online experiment to investigate participants' willingness to participate in fNMES research. This experiment revealed that concerns over potential burns and involuntary muscle movements are significant deterrents to participation. Understanding these anxieties is critical for participant management and expectation setting. Subsequently, two laboratory studies are presented that investigated the facial FFH using fNMES. The first study showed that feelings of happiness and sadness, and changes in peripheral physiology, can be induced by stimulating corresponding facial muscles with 5–seconds of fNMES. The second experiment showed that fNMES-induced smiling alters the perception of ambiguous facial emotions, creating a bias towards happiness, and alters neural correlates of face processing, as measured with event-related potentials (ERPs). In summary, the thesis presents promising results for testing the facial feedback hypothesis with fNMES and provides practical guidelines and recommendations for researchers interested in using fNMES for psychological research

    Cerebrospinal fluid level of proNGF as potential diagnostic biomarker in patients with frontotemporal dementia

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    IntroductionFrontotemporal dementia (FTD) is an extremely heterogeneous and complex neurodegenerative disease, exhibiting different phenotypes, genetic backgrounds, and pathological states. Due to these characteristics, and to the fact that clinical symptoms overlap with those of other neurodegenerative diseases or psychiatric disorders, the diagnosis based only on the clinical evaluation is very difficult. The currently used biomarkers help in the clinical diagnosis, but are insufficient and do not cover all the clinical needs.MethodsBy the means of a new immunoassay, we have measured and analyzed the proNGF levels in 43 cerebrospinal fluids (CSF) from FTD patients, and compared the results to those obtained in CSF from 84 Alzheimer’s disease (AD), 15 subjective memory complaints (SMC) and 13 control subjects.ResultsA statistically significant difference between proNGF levels in FTD compared to AD, SMC and controls subjects was found. The statistical models reveal that proNGF determination increases the accuracy of FTD diagnosis, if added to the clinically validated CSF biomarkers.DiscussionThese results suggest that proNGF could be included in a panel of biomarkers to improve the FTD diagnosis

    Tau pathology in Alzheimer's disease and other dementias : translational approach from in vitro autoradiography to in vivo PET imaging

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    Tauopathies, including Alzheimer's disease (AD), corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP), are complex neurodegenerative disorders characterized by the pathological accumulation of tau proteins in the brain. These often overlapping disorders, with intricate pathologies and growing prevalence, lack definitive treatments, highlighting the necessity for advanced research. Positron emission tomography (PET) imaging aids in the diagnosis and monitoring of diseases, by providing in vivo insights into pathological features. This thesis focused on deciphering the binding properties and brain regional distribution of PET tracers for accurate disease differentiation. Spanning four studies, we aimed to bridge in vitro and in vivo PET data to investigate tau pathology and its association with dementia-related markers such as reactive astrogliosis, peripheral inflammation, and dopaminergic dysfunction. The 2nd generation tau PET tracers, 3H-MK6240 and 3H-PI2620, demonstrated high affinity and specificity in AD post-mortem brain tissues, especially in early-onset AD, compared to controls. 3H-PI2620, 3H-MK6240, and 3HRO948 displayed similar binding patterns in AD tissue, with multiple binding sites and equivalent high affinities (Papers I and II). 3H-PI2620 showed specificity in CBD and PSP tissues, in contrast to 3H-MK6240. However, differentiating CBD from PSP brains with 3H-PI2620 remained challenging in multiple brain regions, potentially due to complex tracer-target interactions (Papers II and III). Reactive astrogliosis PET tracers 3H-Deprenyl and 3H-BU99008 bound primarily to stable distinct high-affinity binding sites in AD, CBD and PSP, but also to transient binding sites, differing by brain region and condition. This pattern implied that these tracers may interact with similar or diverse subtypes or populations of astrocytes, expressing varying ratios of transient sites, which may vary depending on the brain location and the disease (Paper III). Using 3H-FEPE2I, we delineated a reduction in dopamine transporter (DAT) levels within the putamen across CBD, PSP and Parkinson's Disease (PD) brains. Concomitantly, elevated 3H-Raclopride binding reflected higher dopamine D2 receptor (D2R) levels in PSP and PD. Nonetheless, our observations underscored the heterogeneity inherent to these neurodegenerative pathologies, emphasizing the criticality of individual variability in neuropathological manifestations (Paper III). Lastly, we investigated late middle-aged cognitively unimpaired Hispanic individuals, in dichotomous groups of in vivo amyloid-ÎČ (AÎČ) PET (18F-Florbetaben) and plasma neurofilament light (NfL) biomarkers. Our findings suggest that elevated plasma inflammation and tau burden as measured by 18FMK6240, can be detected at early preclinical stages of AD, offering potential for early diagnosis (Paper IV). This thesis underscored the importance of PET imaging in advancing our understanding of tauopathies. The innovative use of multiple PET tracers provided crucial insights into their potential use in clinics to distinguish pathological features of AD, CBD and PSP. The findings emphasized the need for more studies applying a multifaceted approach to studying and managing these complex neurodegenerative disorders, combining advanced imaging techniques with a broad spectrum of biological markers

    Chaudhuri’s Dashboard of Vitals in Parkinson’s syndrome: an unmet need underpinned by real life clinical tests

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    We have recently published the notion of the “vitals” of Parkinson’s, a conglomeration of signs and symptoms, largely nonmotor, that must not be missed and yet often not considered in neurological consultations, with considerable societal and personal detrimental consequences. This “dashboard,” termed the Chaudhuri’s vitals of Parkinson’s, are summarized as 5 key vital symptoms or signs and comprise of (a) motor, (b) nonmotor, (c) visual, gut, and oral health, (d) bone health and falls, and finally (e) comorbidities, comedication, and dopamine agonist side effects, such as impulse control disorders. Additionally, not addressing the vitals also may reflect inadequate management strategies, leading to worsening quality of life and diminished wellness, a new concept for people with Parkinson’s. In this paper, we discuss possible, simple to use, and clinically relevant tests that can be used to monitor the status of these vitals, so that these can be incorporated into clinical practice. We also use the term Parkinson’s syndrome to describe Parkinson’s disease, as the term “disease” is now abandoned in many countries, such as the U.K., reflecting the heterogeneity of Parkinson’s, which is now considered by many as a syndrome

    A review of combined neuromodulation and physical therapy interventions for enhanced neurorehabilitation

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    Rehabilitation approaches for individuals with neurologic conditions have increasingly shifted toward promoting neuroplasticity for enhanced recovery and restoration of function. This review focuses on exercise strategies and non-invasive neuromodulation techniques that target neuroplasticity, including transcranial magnetic stimulation (TMS), vagus nerve stimulation (VNS), and peripheral nerve stimulation (PNS). We have chosen to focus on non-invasive neuromodulation techniques due to their greater potential for integration into routine clinical practice. We explore and discuss the application of these interventional strategies in four neurological conditions that are frequently encountered in rehabilitation settings: Parkinson’s Disease (PD), Traumatic Brain Injury (TBI), stroke, and Spinal Cord Injury (SCI). Additionally, we discuss the potential benefits of combining non-invasive neuromodulation with rehabilitation, which has shown promise in accelerating recovery. Our review identifies studies that demonstrate enhanced recovery through combined exercise and non-invasive neuromodulation in the selected patient populations. We primarily focus on the motor aspects of rehabilitation, but also briefly address non-motor impacts of these conditions. Additionally, we identify the gaps in current literature and barriers to implementation of combined approaches into clinical practice. We highlight areas needing further research and suggest avenues for future investigation, aiming to enhance the personalization of the unique neuroplastic responses associated with each condition. This review serves as a resource for rehabilitation professionals and researchers seeking a comprehensive understanding of neuroplastic exercise interventions and non-invasive neuromodulation techniques tailored for specific diseases and diagnoses

    Cerebrovascular dysfunction in cerebral small vessel disease

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    INTRODUCTION: Cerebral small vessel disease (SVD) is the cause of a quarter of all ischaemic strokes and is postulated to have a role in up to half of all dementias. SVD pathophysiology remains unclear but cerebrovascular dysfunction may be important. If confirmed many licensed medications have mechanisms of action targeting vascular function, potentially enabling new treatments via drug repurposing. Knowledge is limited however, as most studies assessing cerebrovascular dysfunction are small, single centre, single imaging modality studies due to the complexities in measuring cerebrovascular dysfunctions in humans. This thesis describes the development and application of imaging techniques measuring several cerebrovascular dysfunctions to investigate SVD pathophysiology and trial medications that may improve small blood vessel function in SVD. METHODS: Participants with minor ischaemic strokes were recruited to a series of studies utilising advanced MRI techniques to measure cerebrovascular dysfunction. Specifically MRI scans measured the ability of different tissues in the brain to change blood flow in response to breathing carbon dioxide (cerebrovascular reactivity; CVR) and the flow and pulsatility through the cerebral arteries, venous sinuses and CSF spaces. A single centre observational study optimised and established feasibility of the techniques and tested associations of cerebrovascular dysfunctions with clinical and imaging phenotypes. Then a randomised pilot clinical trial tested two medications’ (cilostazol and isosorbide mononitrate) ability to improve CVR and pulsatility over a period of eight weeks. The techniques were then expanded to include imaging of blood brain barrier permeability and utilised in multi-centre studies investigating cerebrovascular dysfunction in both sporadic and monogenetic SVDs. RESULTS: Imaging protocols were feasible, consistently being completed with usable data in over 85% of participants. After correcting for the effects of age, sex and systolic blood pressure, lower CVR was associated with higher white matter hyperintensity volume, Fazekas score and perivascular space counts. Lower CVR was associated with higher pulsatility of blood flow in the superior sagittal sinus and lower CSF flow stroke volume at the foramen magnum. Cilostazol and isosorbide mononitrate increased CVR in white matter. The CVR, intra-cranial flow and pulsatility techniques, alongside blood brain barrier permeability and microstructural integrity imaging were successfully employed in a multi-centre observational study. A clinical trial assessing the effects of drugs targeting blood pressure variability is nearing completion. DISCUSSION: Cerebrovascular dysfunction in SVD has been confirmed and may play a more direct role in disease pathogenesis than previously established risk factors. Advanced imaging measures assessing cerebrovascular dysfunction are feasible in multi-centre studies and trials. Identifying drugs that improve cerebrovascular dysfunction using these techniques may be useful in selecting candidates for definitive clinical trials which require large sample sizes and long follow up periods to show improvement against outcomes of stroke and dementia incidence and cognitive function
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