19 results on '"Estevez‐Fraga, Carlos"'
Search Results
2. Genetic topography and cortical cell loss in Huntington's disease link development and neurodegeneration.
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Estevez-Fraga, Carlos, Altmann, Andre, Parker, Christopher S, Scahill, Rachael I, Costa, Beatrice, Chen, Zhongbo, Manzoni, Claudia, Zarkali, Angeliki, Durr, Alexandra, Roos, Raymund A C, Landwehrmeyer, Bernhard, Leavitt, Blair R, Rees, Geraint, Tabrizi, Sarah J, and McColgan, Peter
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HUNTINGTON disease ,GENE expression ,DIFFUSION magnetic resonance imaging ,NEURODEGENERATION ,TOPOGRAPHY ,GENE targeting - Abstract
Cortical cell loss is a core feature of Huntington's disease (HD), beginning many years before clinical motor diagnosis, during the premanifest stage. However, it is unclear how genetic topography relates to cortical cell loss. Here, we explore the biological processes and cell types underlying this relationship and validate these using cell-specific post-mortem data. Eighty premanifest participants on average 15 years from disease onset and 71 controls were included. Using volumetric and diffusion MRI we extracted HD-specific whole brain maps where lower grey matter volume and higher grey matter mean diffusivity, relative to controls, were used as proxies of cortical cell loss. These maps were combined with gene expression data from the Allen Human Brain Atlas (AHBA) to investigate the biological processes relating genetic topography and cortical cell loss. Cortical cell loss was positively correlated with the expression of developmental genes (i.e. higher expression correlated with greater atrophy and increased diffusivity) and negatively correlated with the expression of synaptic and metabolic genes that have been implicated in neurodegeneration. These findings were consistent for diffusion MRI and volumetric HD-specific brain maps. As wild-type huntingtin is known to play a role in neurodevelopment, we explored the association between wild-type huntingtin (HTT) expression and developmental gene expression across the AHBA. Co-expression network analyses in 134 human brains free of neurodegenerative disorders were also performed. HTT expression was correlated with the expression of genes involved in neurodevelopment while co-expression network analyses also revealed that HTT expression was associated with developmental biological processes. Expression weighted cell-type enrichment (EWCE) analyses were used to explore which specific cell types were associated with HD cortical cell loss and these associations were validated using cell specific single nucleus RNAseq (snRNAseq) data from post-mortem HD brains. The developmental transcriptomic profile of cortical cell loss in preHD was enriched in astrocytes and endothelial cells, while the neurodegenerative transcriptomic profile was enriched for neuronal and microglial cells. Astrocyte-specific genes differentially expressed in HD post-mortem brains relative to controls using snRNAseq were enriched in the developmental transcriptomic profile, while neuronal and microglial-specific genes were enriched in the neurodegenerative transcriptomic profile. Our findings suggest that cortical cell loss in preHD may arise from dual pathological processes, emerging as a consequence of neurodevelopmental changes, at the beginning of life, followed by neurodegeneration in adulthood, targeting areas with reduced expression of synaptic and metabolic genes. These events result in age-related cell death across multiple brain cell types. [ABSTRACT FROM AUTHOR]
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- 2023
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3. Progressive alterations in white matter microstructure across the timecourse of Huntington's disease.
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Estevez‐Fraga, Carlos, Elmalem, Michael S., Papoutsi, Marina, Durr, Alexandra, Rees, Elin M., Hobbs, Nicola Z., Roos, Raymund A. C., Landwehrmeyer, Bernhard, Leavitt, Blair R., Langbehn, Douglas R., Scahill, Rachael I., Rees, Geraint, Tabrizi, Sarah J., and Gregory, Sarah
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- 2023
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4. Huntington's Disease Clinical Trials Corner: August 2023.
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Estevez-Fraga, Carlos, Tabrizi, Sarah J., and Wild, Edward J.
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HUNTINGTON disease ,CLINICAL trials - Abstract
In this edition of the Huntington's Disease Clinical Trials Corner, we expand on the GENERATION HD2 (tominersen) and on the Asklepios Biopharmaceutical/BrainVectis trial with AB-1001. We also comment on the recent findings from the PROOF-HD trial, and list all currently registered and ongoing clinical trials in Huntington's disease. [ABSTRACT FROM AUTHOR]
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- 2023
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5. Intellectual enrichment and genetic modifiers of cognition and brain volume in Huntington's disease.
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Papoutsi, Marina, Flower, Michael, Moss, Davina J. Hensman, Holmans, Peter, Estevez-Fraga, Carlos, Johnson, Eileanoir B., Scahill, Rachael I., Rees, Geraint, Langbehn, Douglas, and Tabrizi, Sarah J.
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- 2022
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6. Neurofilament light-associated connectivity in young-adult Huntington's disease is related to neuronal genes.
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McColgan, Peter, Gregory, Sarah, Zeun, Paul, Zarkali, Angeliki, Johnson, Eileanoir B, Parker, Christopher, Fayer, Kate, Lowe, Jessica, Nair, Akshay, Estevez-Fraga, Carlos, Papoutsi, Marina, Zhang, Hui, Scahill, Rachael I, Tabrizi, Sarah J, and Rees, Geraint
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HUNTINGTON disease ,CYTOPLASMIC filaments ,PATHOLOGY ,LARGE-scale brain networks ,FUNCTIONAL connectivity - Abstract
Upregulation of functional network connectivity in the presence of structural degeneration is seen in the premanifest stages of Huntington's disease (preHD) 10-15 years from clinical diagnosis. However, whether widespread network connectivity changes are seen in gene carriers much further from onset has yet to be explored. We characterized functional network connectivity throughout the brain and related it to a measure of disease pathology burden (CSF neurofilament light, NfL) and measures of structural connectivity in asymptomatic gene carriers, on average 24 years from onset. We related these measurements to estimates of cortical and subcortical gene expression. We found no overall differences in functional (or structural) connectivity anywhere in the brain comparing control and preHD participants. However, increased functional connectivity, particularly between posterior cortical areas, correlated with increasing CSF NfL level in preHD participants. Using the Allen Human Brain Atlas and expression-weighted cell-type enrichment analysis, we demonstrated that this functional connectivity upregulation occurred in cortical regions associated with regional expression of genes specific to neuronal cells. This relationship was validated using single-nucleus RNAseq data from post-mortem Huntington's disease and control brains showing enrichment of neuronal-specific genes that are differentially expressed in Huntington's disease. Functional brain networks in asymptomatic preHD gene carriers very far from disease onset show evidence of upregulated connectivity correlating with increased disease burden. These changes occur among brain areas that show regional expression of genes specific to neuronal GABAergic and glutamatergic cells. [ABSTRACT FROM AUTHOR]
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- 2022
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7. Lumbar puncture safety and tolerability in premanifest and manifest Huntington's disease: a multi-analysis cross-sectional study.
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Hassan, Yara Refaat, Brogueira Rodrigues, Filipe, Zeun, Paul, Byrne, Lauren M., Estevez-Fraga, Carlos, Tortelli, Rosanna, Scahill, Rachael I., Wild, Edward J., and Tabrizi, Sarah J.
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HUNTINGTON disease ,LUMBAR puncture ,CROSS-sectional method ,BIOMARKERS ,BACKACHE - Abstract
Lumbar puncture (LP) has become increasingly common for people with Huntington's disease (HD) both to administer intrathecal investigational medicinal products and to collect cerebrospinal fluid to develop biological markers to track disease stage and progression. We aimed to investigate the safety profile of LP in people with HD, building on a recently published work by increasing the sample size and more specifically, increasing the representation of the premanifest population and healthy controls. We conducted a multi-study cross-sectional analysis including eligible participants from the HDClarity (304 Huntington's disease gene expansion carriers and 91 controls) and HD-YAS studies (54 premanifest and 48 controls), enrolled between February 2016 and September 2019. We investigated the odds of any adverse events, headaches, and back pain independently. Intergroup comparisons and adjusted event odds were derived using hierarchical logistic regressions. A total of 669 LP procedures involving 497 participants were included in this analysis. There were 184 (27.5%) LP procedures associated with one or more adverse events. The two most common adverse events were: post LP headache and back pain. Younger age and female gender were found to be associated with a higher risk of developing adverse events. There was no difference in the rate of adverse events between the disease subgroups after adjusting for covariates such as age and gender. Our results suggest that the LP is safe and tolerable in premanifest and manifest HD subjects, providing useful reassurance about the procedure to the HD community. [ABSTRACT FROM AUTHOR]
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- 2022
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8. Huntington's Disease Clinical Trials Corner: November 2022.
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Estevez-Fraga, Carlos, Tabrizi, Sarah J., and Wild, Edward J.
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HUNTINGTON disease ,CLINICAL trials - Abstract
In this edition of the Huntington's Disease Clinical Trials Corner, we expand on the PIVOT HD (PTC518), and SIGNAL (pepinemab) trials, and list all currently registered and ongoing clinical trials in Huntington's disease. We also introduce a 'breaking news' section highlighting recent updates about the SELECT HD, uniQure AMT-130, and VIBRANT HD clinical trials. [ABSTRACT FROM AUTHOR]
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- 2022
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9. Huntington's Disease Clinical Trials Corner: April 2022.
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Estevez-Fraga, Carlos, Rodrigues, Filipe B., Tabrizi, Sarah J., and Wild, Edward J.
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HUNTINGTON disease ,CLINICAL trials - Abstract
In this edition of the Huntington's Disease Clinical Trials Corner we expand on GENERATION HD1, PRECISION-HD1 and PRECISION-HD2, SELECT-HD, and VIBRANT-HD trials, and list all currently registered and ongoing clinical trials in Huntington's disease. [ABSTRACT FROM AUTHOR]
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- 2022
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10. Reply to: Juvenile PLA2G6‐parkinsonism due to Indian 'Asian' p.R741Q mutation, and response to STN DBS.
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Magrinelli, Francesca, Rajapaksha, Ishani, Kobylecki, Christopher, Latorre, Anna, Mulroy, Eoin, Estevez‐Fraga, Carlos, Houlden, Henry, Tinazzi, Michele, and Bhatia, Kailash P.
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- 2022
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11. Dissecting the Phenotype and Genotype of PLA2G6-Related Parkinsonism.
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Magrinelli, Francesca, Mehta, Sahil, Di Lazzaro, Giulia, Latorre, Anna, Edwards, Mark J., Balint, Bettina, Basu, Purba, Kobylecki, Christopher, Groppa, Sergiu, Hegde, Anaita, Mulroy, Eoin, Estevez‐Fraga, Carlos, Arora, Anshita, Kumar, Hrishikesh, Schneider, Susanne A., Lewis, Patrick A., Jaunmuktane, Zane, Revesz, Tamas, Gandhi, Sonia, and Wood, Nicholas W.
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Background: Complex parkinsonism is the commonest phenotype in late-onset PLA2G6-associated neurodegeneration.Objectives: The aim of this study was to deeply characterize phenogenotypically PLA2G6-related parkinsonism in the largest cohort ever reported.Methods: We report 14 new cases of PLA2G6-related parkinsonism and perform a systematic literature review.Results: PLA2G6-related parkinsonism shows a fairly distinct phenotype based on 86 cases from 68 pedigrees. Young onset (median age, 23.0 years) with parkinsonism/dystonia, gait/balance, and/or psychiatric/cognitive symptoms were common presenting features. Dystonia occurred in 69.4%, pyramidal signs in 77.2%, myoclonus in 65.2%, and cerebellar signs in 44.6% of cases. Early bladder overactivity was present in 71.9% of cases. Cognitive impairment affected 76.1% of cases and psychiatric features 87.1%, the latter being an isolated presenting feature in 20.1%. Parkinsonism was levodopa responsive but complicated by early, often severe dyskinesias. Five patients benefited from deep brain stimulation. Brain magnetic resonance imaging findings included cerebral (49.3%) and/or cerebellar (43.2%) atrophy, but mineralization was evident in only 28.1%. Presynaptic dopaminergic terminal imaging was abnormal in all where performed. Fifty-four PLA2G6 mutations have hitherto been associated with parkinsonism, including four new variants reported in this article. These are mainly nontruncating, which may explain the phenotypic heterogeneity of childhood- and late-onset PLA2G6-associated neurodegeneration. In five deceased patients, median disease duration was 13.0 years. Brain pathology in three cases showed mixed Lewy and tau pathology.Conclusions: Biallelic PLA2G6 mutations cause early-onset parkinsonism associated with dystonia, pyramidal and cerebellar signs, myoclonus, and cognitive impairment. Early psychiatric manifestations and bladder overactivity are common. Cerebro/cerebellar atrophy are frequent magnetic resonance imaging features, whereas brain iron deposition is not. Early, severe dyskinesias are a tell-tale sign. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]- Published
- 2022
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12. X‐Linked Parkinsonism: Phenotypic and Genetic Heterogeneity.
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Di Lazzaro, Giulia, Magrinelli, Francesca, Estevez‐Fraga, Carlos, Valente, Enza M., Pisani, Antonio, and Bhatia, Kailash P.
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X‐linked parkinsonism encompasses rare heterogeneous disorders mainly inherited as a recessive trait, therefore being more prevalent in males. Recent developments have revealed a complex underlying panorama, including a spectrum of disorders in which parkinsonism is variably associated with additional neurological and non‐neurological signs. In particular, a childhood‐onset encephalopathy with epilepsy and/or cognitive disability is the most common feature. Their genetic basis is also heterogeneous, with many causative genes and different mutation types ranging from "classical" coding variants to intronic repeat expansions. In this review, we provide an updated overview of the phenotypic and genetic spectrum of the most relevant X‐linked parkinsonian syndromes, namely X‐linked dystonia‐parkinsonism (XDP, Lubag disease), fragile X‐associated tremor/ataxia syndrome (FXTAS), beta‐propeller protein‐associated neurodegeneration (BPAN, NBIA/PARK‐WDR45), Fabry disease, Waisman syndrome, methyl CpG‐binding protein 2 (MeCP2) spectrum disorder, phosphoglycerate kinase‐1 deficiency syndrome (PGK1) and X‐linked parkinsonism and spasticity (XPDS). All clinical and radiological features reported in the literature have been reviewed. Epilepsy occasionally represents the symptom of onset, predating parkinsonism even by a few years; action tremor is another common feature along with akinetic‐rigid parkinsonism. A focus on the genetic background and its pathophysiological implications is provided. The pathogenesis of these disorders ranges from well‐defined metabolic alterations (PGK1) to non‐specific lysosomal dysfunctions (XPDS) and vesicular trafficking alterations (Waisman syndrome). However, in other cases it still remains poorly defined. Recognition of the phenotypic and genetic heterogeneity of X‐linked parkinsonism has important implications for diagnosis, management, and genetic counseling. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]
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- 2021
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13. Composite UHDRS Correlates With Progression of Imaging Biomarkers in Huntington's Disease.
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Estevez‐Fraga, Carlos, Scahill, Rachael I., Durr, Alexandra, Leavitt, Blair R., Roos, Raymund A.C., Langbehn, Douglas R., Rees, Geraint, Gregory, Sarah, and Tabrizi, Sarah J.
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Background: The composite Unified Huntington's Disease Rating Scale (cUHDRS) is a multidimensional measure of progression in Huntington's disease (HD) being used as a primary outcome in clinical trials investigating potentially disease‐modifying huntingtin‐lowering therapies. Objective: Evaluating volumetric and structural connectivity correlates of the cUHDRS. Methods: One hundred and nineteen premanifest and 119 early‐HD participants were included. Gray and white matter (WM) volumes were correlated with cUHDRS cross‐sectionally and longitudinally using voxel‐based morphometry. Correlations between baseline fractional anisotropy (FA); mean, radial, and axial diffusivity; and baseline cUHDRS were examined using tract‐based spatial statistics. Results: Worse performance in the cUHDRS over time correlated with longitudinal volume decreases in the occipito‐parietal cortex and centrum semiovale, whereas lower baseline scores correlated with decreased volume in the basal ganglia and surrounding WM. Lower cUHDRS scores were also associated with reduced FA and increased diffusivity at baseline. Conclusion: The cUHDRS correlates with imaging biomarkers and tracks atrophy progression in HD supporting its biological relevance. © 2021 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]
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- 2021
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14. Disease Onset in Huntington's Disease: When Is the Conversion?
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Oosterloo, Mayke, Greef, Bianca T.A., Bijlsma, Emilia K., Durr, Alexandra, Tabrizi, Sarah J., Estevez‐Fraga, Carlos, Die‐Smulders, Christine E.M., and Roos, Raymund A.C.
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HUNTINGTON disease ,SYMPTOMS - Abstract
Background: Determination of disease onset in Huntington's disease is made by clinical experience. The diagnostic confidence level is an assessment regarding the certainty about the clinical diagnosis based on motor signs. A level of 4 means the rater has ≥99% confidence motor abnormalities are unequivocal signs of disease. However, it does not state which motor abnormalities are signs of disease and how many must be present. Objective: Our aim is to explore how accurate the diagnostic confidence level is in estimating disease onset using the Enroll‐HD data set. For clinical disease onset we use a cut‐off total motor score >5 of the Unified Huntington's Disease Rating Scale. This score is used in the TRACK‐HD study, with ≤5 indicating no substantial motor signs in premanifests. Methods: At baseline premanifest participants who converted to manifest (converters) and non‐converters were compared for clinical symptoms and diagnostic confidence level. Clinical symptoms and diagnostic confidence levels were longitudinally displayed in converters. Results: Of 3731 eligible participants, 455 were converters and 3276 non‐converters. Baseline diagnostic confidence levels were significantly higher in converters compared to non‐converters (P < 0.001). 232 (51%) converters displayed a baseline motor score >5 (mean = 6.7). Converters had significantly more baseline clinical symptoms, and higher disease burden compared to non‐converters (P < 0.001). Diagnostic confidence level before disease onset ranged between 1 and 3 in converters. Conclusions: According to this data the diagnostic confidence level is not an accurate instrument to determine phenoconversion. With trials evaluating disease modifying therapies it is important to develop more reliable diagnostic criteria. [ABSTRACT FROM AUTHOR]
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- 2021
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15. Diffusion imaging in Huntington's disease: comprehensive review.
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Estevez-Fraga, Carlos, Scahil, Rachael, Rees, Geraint, Tabrizi, Sarah J., Gregory, Sarah, and Scahill, Rachael
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HUNTINGTON disease ,DIFFUSION magnetic resonance imaging ,DIFFUSION ,WHITE matter (Nerve tissue) ,GRAY matter (Nerve tissue) ,SPINOCEREBELLAR ataxia ,BASAL ganglia diseases - Abstract
Huntington's disease (HD) is a monogenic disorder with 100% penetrance. With the advent of genetic testing in adults, disease-related, structural brain changes can be investigated from the earliest, premorbid stages of HD. While examining macrostructural change characterises global neuronal damage, investigating microstructural alterations provides information regarding brain organisation and its underlying biological properties. Diffusion MRI can be used to track the progression of microstructural anomalies in HD decades prior to clinical disease onset, providing a greater understanding of neurodegeneration. Multiple approaches, including voxelwise, region of interest and tractography, have been used in HD cohorts, showing a centrifugal pattern of white matter (WM) degeneration starting from deep brain areas, which is consistent with neuropathological studies. The corpus callosum, longer WM tracts and areas that are more densely connected, in particular the sensorimotor network, also tend to be affected early during premanifest stages. Recent evidence supports the routine inclusion of diffusion analyses within clinical trials principally as an additional measure to improve understanding of treatment effects, while the advent of novel techniques such as multitissue compartment models and connectomics can help characterise the underpinnings of progressive functional decline in HD. [ABSTRACT FROM AUTHOR]
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- 2021
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16. Therapeutic strategies for Huntington's disease.
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Estevez-Fraga, Carlos, Flower, Michael D., and Tabrizi, Sarah J.
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- 2020
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17. Current Methods for the Treatment and Prevention of Drug-Induced Parkinsonism and Tardive Dyskinesia in the Elderly.
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Estevez-Fraga, Carlos, Zeun, Paul, and López-Sendón Moreno, Jose Luis
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HETEROCYCLIC compounds ,MEMBRANE transport proteins ,DOPAMINE antagonists ,MEDICAL practice ,TARDIVE dyskinesia ,PARKINSONIAN disorders ,PREVENTION ,THERAPEUTICS - Abstract
Drug-induced parkinsonism (DIP) and tardive dyskinesia (TD) are iatrogenic consequences of antidopaminergic drugs. Both are particularly prevalent among the elderly and those with dementia. However, despite their prevalence, these disorders are often overlooked. Both entities share risk factors, physiopathological mechanisms and, to some degree, therapeutic approaches. Withdrawing the causal agent, reducing the dose or switching to a less potent antidopaminergic drug should be the first therapeutic options. Here we review both entities and emerging therapies including the recently approved drugs deutetrabenazine and valbenazine. We discuss relevant aspects for clinical practice such as new diagnostic techniques and the latest advances in the understanding of DIP and TD. [ABSTRACT FROM AUTHOR]
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- 2018
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18. Disentangling the Connection Between Neurodevelopment and Neurodegeneration in Huntington's Disease.
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Estevez‐Fraga, Carlos and Tabrizi, Sarah J.
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- 2022
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19. Quality of Chronic Anticoagulation Control in Patients with Intracranial Haemorrhage due to Vitamin K Antagonists.
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Estevez-Fraga, Carlos, Molina-Sanchez, Maria, Alvarez-Velasco, Rodrigo, Agüero-Rabes, Pablo, Crespo-Araico, Leticia, Viedma-Guiard, Elena, Cruz-Culebras, Antonio, Matute, Consuelo, Vera, Rocio, De Felipe-Mimbrera, Alicia, and Masjuan Vallejo, Jaime
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ATRIAL fibrillation ,CEREBRAL hemorrhage ,CONFIDENCE intervals ,PROSTHETIC heart valves ,LONGITUDINAL method ,RISK assessment ,TIME ,VITAMIN K ,INTERNATIONAL normalized ratio ,STROKE units ,CHEMICAL inhibitors ,DISEASE risk factors - Abstract
Introduction. Patients treated with vitamin K antagonists (VKA) are at increased risk of intracranial haemorrhage (ICH). The purpose of our study was to determine the quality of previous anticoagulation control in patients with VKA-associated ICH. Materials and Methods. We prospectively assessed every consecutive patient admitted to our stroke unit with VKA-associated ICH between 2013 and 2016. Demographic, clinical, and radiological variables, as well as consecutive international normalized ratios (INR) during 7 previous months, were extracted. Time in therapeutic range (TTR), time over range (TOR), time below range (TBR), and percentage of INR within range (PINRR) were calculated. Results and Discussion. The study population comprised 53 patients. Mean age was 79 years; 42% were women. Forty-eight patients had atrial fibrillation (AF) and 5 mechanical prosthetic valves. Therapeutic or infratherapeutic INR on arrival was detected in 64.4% of patients (95% CI 2.7 to 3.2). TTR was 67.8% (95% CI: 60.2 to 75.6 %) and PINRR was 75% (95% CI: 49.9-100). TOR was 17.2% (95% CI: 10.4 to 23.9% ) and TBR was 17% (95% CI: 10.6 to 23.9%). Conclusion. VKA-associated ICH happens usually in the context of good chronic anticoagulation control. Newer risk assessment methods are required. [ABSTRACT FROM AUTHOR]
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- 2018
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