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5. Heterozygous UCHL1 loss-of-function variants cause a neurodegenerative disorder with spasticity, ataxia, neuropathy, and optic atrophy

Author

Park, Joohyun, primary, Tucci, Arianna, additional, Cipriani, Valentina, additional, Demidov, German, additional, Rocca, Clarissa, additional, Senderek, Jan, additional, Butryn, Michaela, additional, Velic, Ana, additional, Lam, Tanya, additional, Galanaki, Evangelia, additional, Cali, Elisa, additional, Vestito, Letizia, additional, Maroofian, Reza, additional, Deininger, Natalie, additional, Rautenberg, Maren, additional, Admard, Jakob, additional, Hahn, Gesa-Astrid, additional, Bartels, Claudius, additional, van Os, Nienke J.H., additional, Horvath, Rita, additional, Chinnery, Patrick F., additional, Tiet, May Yung, additional, Hewamadduma, Channa, additional, Hadjivassiliou, Marios, additional, Downes, Susan M., additional, Németh, Andrea H., additional, Tofaris, George K., additional, Wood, Nicholas W., additional, Hayer, Stefanie N., additional, Bender, Friedemann, additional, Menden, Benita, additional, Cordts, Isabell, additional, Klein, Katrin, additional, Nguyen, Huu Phuc, additional, Krauss, Joachim K., additional, Blahak, Christian, additional, Strom, Tim M., additional, Sturm, Marc, additional, van de Warrenburg, Bart, additional, Lerche, Holger, additional, Maček, Boris, additional, Synofzik, Matthis, additional, Ossowski, Stephan, additional, Timmann, Dagmar, additional, Wolf, Marc E., additional, Smedley, Damian, additional, Riess, Olaf, additional, Schöls, Ludger, additional, Houlden, Henry, additional, Haack, Tobias B., additional, and Hengel, Holger, additional

Published
2023
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7. Detailed Analysis of ITPR1 Missense Variants Guides Diagnostics and Therapeutic Design.

Author

Tolonen, Jussi Pekka, Parolin Schnekenberg, Ricardo, McGowan, Simon, Sims, David, McEntagart, Meriel, Elmslie, Frances, Shears, Debbie, Stewart, Helen, Tofaris, George K., Dabir, Tabib, Morrison, Patrick J., Johnson, Diana, Hadjivassiliou, Marios, Ellard, Sian, Shaw‐Smith, Charles, Znaczko, Anna, Dixit, Abhijit, Suri, Mohnish, Sarkar, Ajoy, and Harrison, Rachel E.

Abstract

Background: The ITPR1 gene encodes the inositol 1,4,5‐trisphosphate (IP3) receptor type 1 (IP3R1), a critical player in cerebellar intracellular calcium signaling. Pathogenic missense variants in ITPR1 cause congenital spinocerebellar ataxia type 29 (SCA29), Gillespie syndrome (GLSP), and severe pontine/cerebellar hypoplasia. The pathophysiological basis of the different phenotypes is poorly understood. Objectives: We aimed to identify novel SCA29 and GLSP cases to define core phenotypes, describe the spectrum of missense variation across ITPR1, standardize the ITPR1 variant nomenclature, and investigate disease progression in relation to cerebellar atrophy. Methods: Cases were identified using next‐generation sequencing through the Deciphering Developmental Disorders study, the 100,000 Genomes project, and clinical collaborations. ITPR1 alternative splicing in the human cerebellum was investigated by quantitative polymerase chain reaction. Results: We report the largest, multinational case series of 46 patients with 28 unique ITPR1 missense variants. Variants clustered in functional domains of the protein, especially in the N‐terminal IP3‐binding domain, the carbonic anhydrase 8 (CA8)‐binding region, and the C‐terminal transmembrane channel domain. Variants outside these domains were of questionable clinical significance. Standardized transcript annotation, based on our ITPR1 transcript expression data, greatly facilitated analysis. Genotype–phenotype associations were highly variable. Importantly, while cerebellar atrophy was common, cerebellar volume loss did not correlate with symptom progression. Conclusions: This dataset represents the largest cohort of patients with ITPR1 missense variants, expanding the clinical spectrum of SCA29 and GLSP. Standardized transcript annotation is essential for future reporting. Our findings will aid in diagnostic interpretation in the clinic and guide selection of variants for preclinical studies. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Published
2024
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12. Heterozygous UCHL1 loss-of-function variants cause a neurodegenerative disorder with spasticity, ataxia, neuropathy, and optic atrophy

Author

Park, Joohyun, primary, Tucci, Arianna, additional, Cipriani, Valentina, additional, Demidov, German, additional, Rocca, Clarissa, additional, Senderek, Jan, additional, Butryn, Michaela, additional, Velic, Ana, additional, Lam, Tanya, additional, Galanaki, Evangelia, additional, Cali, Elisa, additional, Vestito, Letizia, additional, Maroofian, Reza, additional, Deininger, Natalie, additional, Rautenberg, Maren, additional, Admard, Jakob, additional, Hahn, Gesa-Astrid, additional, Bartels, Claudius, additional, van Os, Nienke J.H., additional, Horvath, Rita, additional, Chinnery, Patrick F., additional, Tiet, May Yung, additional, Hewamadduma, Channa, additional, Hadjivassiliou, Marios, additional, Tofaris, George K., additional, Wood, Nicholas W., additional, Hayer, Stefanie N., additional, Bender, Friedemann, additional, Menden, Benita, additional, Cordts, Isabell, additional, Klein, Katrin, additional, Nguyen, Huu Phuc, additional, Krauss, Joachim K., additional, Blahak, Christian, additional, Strom, Tim M., additional, Sturm, Marc, additional, van de Warrenburg, Bart, additional, Lerche, Holger, additional, Maček, Boris, additional, Synofzik, Matthis, additional, Ossowski, Stephan, additional, Timmann, Dagmar, additional, Wolf, Marc E., additional, Smedley, Damian, additional, Riess, Olaf, additional, Schöls, Ludger, additional, Houlden, Henry, additional, Haack, Tobias B., additional, Hengel, Holger, additional, Ambrose, J.C., additional, Arumugam, P., additional, Baple, E.L., additional, Bleda, M., additional, Boardman-Pretty, F., additional, Boissiere, J.M., additional, Boustred, C.R., additional, Brittain, H., additional, Caulfield, M.J., additional, Chan, G.C., additional, Craig, C.E.H., additional, Daugherty, L.C., additional, de Burca, A., additional, Devereau, A., additional, Elgar, G., additional, Foulger, R.E., additional, Fowler, T., additional, Furió-Tarí, P., additional, Hackett, J.M., additional, Halai, D., additional, Hamblin, A., additional, Henderson, S., additional, Holman, J.E., additional, Hubbard, T.J.P., additional, Ibáñez, K., additional, Jackson, R., additional, Jones, L.J., additional, Kasperaviciute, D., additional, Kayikci, M., additional, Lahnstein, L., additional, Lawson, K., additional, Leigh, S.E.A., additional, Leong, I.U.S., additional, Lopez, F.J., additional, Maleady-Crowe, F., additional, Mason, J., additional, McDonagh, E.M., additional, Moutsianas, L., additional, Mueller, M., additional, Murugaesu, N., additional, Need, A.C., additional, Odhams, C.A., additional, Patch, C., additional, Perez-Gil, D., additional, Polychronopoulos, D., additional, Pullinger, J., additional, Rahim, T., additional, Rendon, A., additional, Riesgo-Ferreiro, P., additional, Rogers, T., additional, Ryten, M., additional, Savage, K., additional, Sawant, K., additional, Scott, R.H., additional, Siddiq, A., additional, Sieghart, A., additional, Smedley, D., additional, Smith, K.R., additional, Sosinsky, A., additional, Spooner, W., additional, Stevens, H.E., additional, Stuckey, A., additional, Sultana, R., additional, Thomas, E.R.A., additional, Thompson, S.R., additional, Tregidgo, C., additional, Tucci, A., additional, Walsh, E., additional, Watters, S.A., additional, Welland, M.J., additional, Williams, E., additional, Witkowska, K., additional, Wood, S.M., additional, and Zarowiecki, M., additional

Published
2022
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13. The Phenotypic Continuum of ATP1A3-Related Disorders

Author

Vezyroglou, Aikaterini, primary, Akilapa, Rhoda, additional, Barwick, Katy, additional, Koene, Saskia, additional, Brownstein, Catherine A., additional, Holder-Espinasse, Muriel, additional, Fry, Andrew E., additional, Németh, Andrea H., additional, Tofaris, George K., additional, Hay, Eleanor, additional, Hughes, Imelda, additional, Mansour, Sahar, additional, Mordekar, Santosh R., additional, Splitt, Miranda, additional, Turnpenny, Peter D., additional, Demetriou, Demetria, additional, Koopmann, Tamara T., additional, Ruivenkamp, Claudia A.L., additional, Agrawal, Pankaj B., additional, Carr, Lucinda, additional, Clowes, Virginia, additional, Ghali, Neeti, additional, Holder, Susan Elizabeth, additional, Radley, Jessica, additional, Male, Alison, additional, Sisodiya, Sanjay M., additional, Kurian, Manju A., additional, Cross, J. Helen, additional, and Balasubramanian, Meena, additional

Published
2022
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19. Syndrome of cerebral venous sinus thrombosis and thrombocytopenia after vaccination for COVID-19

Author

Soleimani, Babak, primary, Turaga, Sanchit, additional, Khan, Dalia, additional, Davies, Claire, additional, Duodu, Yaw, additional, Botcherby, Edward, additional, Plaha, Puneet, additional, Apostolopoulos, Vasileios, additional, Kousin-Ezewu, Onajite, additional, Jenkins, Damian, additional, Webb, Alastair, additional, and Tofaris, George K, additional

Published
2021
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22. Heterozygous UCHL1loss-of-function variants cause a neurodegenerative disorder with spasticity, ataxia, neuropathy, and optic atrophy

Author

Park, Joohyun, Tucci, Arianna, Cipriani, Valentina, Demidov, German, Rocca, Clarissa, Senderek, Jan, Butryn, Michaela, Velic, Ana, Lam, Tanya, Galanaki, Evangelia, Cali, Elisa, Vestito, Letizia, Maroofian, Reza, Deininger, Natalie, Rautenberg, Maren, Admard, Jakob, Hahn, Gesa-Astrid, Bartels, Claudius, van Os, Nienke J.H., Horvath, Rita, Chinnery, Patrick F., Tiet, May Yung, Hewamadduma, Channa, Hadjivassiliou, Marios, Tofaris, George K., Ambrose, J.C., Arumugam, P., Baple, E.L., Bleda, M., Boardman-Pretty, F., Boissiere, J.M., Boustred, C.R., Brittain, H., Caulfield, M.J., Chan, G.C., Craig, C.E.H., Daugherty, L.C., de Burca, A., Devereau, A., Elgar, G., Foulger, R.E., Fowler, T., Furió-Tarí, P., Hackett, J.M., Halai, D., Hamblin, A., Henderson, S., Holman, J.E., Hubbard, T.J.P., Ibáñez, K., Jackson, R., Jones, L.J., Kasperaviciute, D., Kayikci, M., Lahnstein, L., Lawson, K., Leigh, S.E.A., Leong, I.U.S., Lopez, F.J., Maleady-Crowe, F., Mason, J., McDonagh, E.M., Moutsianas, L., Mueller, M., Murugaesu, N., Need, A.C., Odhams, C.A., Patch, C., Perez-Gil, D., Polychronopoulos, D., Pullinger, J., Rahim, T., Rendon, A., Riesgo-Ferreiro, P., Rogers, T., Ryten, M., Savage, K., Sawant, K., Scott, R.H., Siddiq, A., Sieghart, A., Smedley, D., Smith, K.R., Sosinsky, A., Spooner, W., Stevens, H.E., Stuckey, A., Sultana, R., Thomas, E.R.A., Thompson, S.R., Tregidgo, C., Tucci, A., Walsh, E., Watters, S.A., Welland, M.J., Williams, E., Witkowska, K., Wood, S.M., Zarowiecki, M., Wood, Nicholas W., Hayer, Stefanie N., Bender, Friedemann, Menden, Benita, Cordts, Isabell, Klein, Katrin, Nguyen, Huu Phuc, Krauss, Joachim K., Blahak, Christian, Strom, Tim M., Sturm, Marc, van de Warrenburg, Bart, Lerche, Holger, Maček, Boris, Synofzik, Matthis, Ossowski, Stephan, Timmann, Dagmar, Wolf, Marc E., Smedley, Damian, Riess, Olaf, Schöls, Ludger, Houlden, Henry, Haack, Tobias B., and Hengel, Holger

Abstract

Biallelic variants in UCHL1have been associated with a progressive early-onset neurodegenerative disorder, autosomal recessive spastic paraplegia type 79. In this study, we investigated heterozygous UCHL1variants on the basis of results from cohort-based burden analyses.

Published
2022
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25. Serum neuronal exosomes predict and differentiate Parkinson’s disease from atypical parkinsonism

Author

Jiang, Cheng, primary, Hopfner, Franziska, additional, Katsikoudi, Antigoni, additional, Hein, Robert, additional, Catli, Candan, additional, Evetts, Samuel, additional, Huang, Yongzhi, additional, Wang, Hong, additional, Ryder, John W, additional, Kuhlenbaeumer, Gregor, additional, Deuschl, Guenther, additional, Padovani, Alessandro, additional, Berg, Daniela, additional, Borroni, Barbara, additional, Hu, Michele T, additional, Davis, Jason J, additional, and Tofaris, George K, additional

Published
2020
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27. Stem cell modeling of mitochondrial parkinsonism reveals key functions of OPA1

Author

Jonikas, Mindaugas, Madill, Martin, Mathy, Alexandre, Zekoll, Theresa, Zois, Christos E, Wigfield, Simon, Kurzawa-Akanbi, Marzena, Browne, Cathy, Sims, David, Chinnery, Patrick F, Cowley, Sally A, Tofaris, George K, Tofaris, George K [0000-0002-9252-5933], and Apollo - University of Cambridge Repository

Subjects
Membrane Potential, Mitochondrial, endocrine system, Optic Atrophy, Parkinsonian Disorders, Induced Pluripotent Stem Cells, Humans, DNA, Mitochondrial, Research Articles, eye diseases, Oxidative Phosphorylation, Research Article, GTP Phosphohydrolases, Mitochondria
Abstract

OBJECTIVE: Defective mitochondrial function attributed to optic atrophy 1 (OPA1) mutations causes primarily optic atrophy and, less commonly, neurodegenerative syndromes. The pathomechanism by which OPA1 mutations trigger diffuse loss of neurons in some, but not all, patients is unknown. Here, we used a tractable induced pluripotent stem cell (iPSC)-based model to capture the biology of OPA1 haploinsufficiency in cases presenting with classic eye disease versus syndromic parkinsonism. METHODS: iPSCs were generated from 2 patients with OPA1 haploinsufficiency and 2 controls and differentiated into dopaminergic neurons. Metabolic profile was determined by extracellular flux analysis, respiratory complex levels using immunoblotting, and complex I activity by a colorimetric assay. Mitochondria were examined by transmission electron microscopy. Mitochondrial DNA copy number and deletions were assayed using long-range PCR. Mitochondrial membrane potential was measured by tetramethylrhodamine methyl ester uptake, and mitochondrial fragmentation was assessed by confocal microscopy. Exome sequencing was used to screen for pathogenic variants. RESULTS: OPA1 haploinsufficient iPSCs differentiated into dopaminergic neurons and exhibited marked reduction in OPA1 protein levels. Loss of OPA1 caused a late defect in oxidative phosphorylation, reduced complex I levels, and activity without a significant change in the ultrastructure of mitochondria. Loss of neurons in culture recapitulated dopaminergic degeneration in syndromic disease and correlated with mitochondrial fragmentation. INTERPRETATION: OPA1 levels maintain oxidative phosphorylation in iPSC-derived neurons, at least in part, by regulating the stability of complex I. Severity of OPA1 disease associates primarily with the extent of OPA1-mediated fusion, suggesting that activation of this mechanism or identification of its genetic modifiers may have therapeutic or prognostic value. Ann Neurol 2018;83:915-925.

Published
2018

32. Serum neuronal exosomes predict and differentiate Parkinson's disease from atypical parkinsonism.

Author

Cheng Jiang, Hopfner, Franziska, Katsikoudi, Antigoni, Hein, Robert, Catli, Candan, Evetts, Samuel, Yongzhi Huang, Hong Wang, Ryder, John W., Kuhlenbaeumer, Gregor, Deuschl, Guenther, Padovani, Alessandro, Berg, Daniela, Borroni, Barbara, Hu, Michele T., Davis, Jason J., Tofaris, George K., Jiang, Cheng, Huang, Yongzhi, and Wang, Hong

Subjects
PARKINSON'S disease, PROGRESSIVE supranuclear palsy, FRONTOTEMPORAL lobar degeneration, PARKINSONIAN disorders, EXOSOMES, DNA-binding proteins, NEURAL cell adhesion molecule, PARKINSON'S disease diagnosis, RESEARCH, NEURONS, CROSS-sectional method, RESEARCH methodology, DIFFERENTIAL diagnosis, EVALUATION research, MEDICAL cooperation, COMPARATIVE studies, RESEARCH funding, NEURODEGENERATION
Abstract

Objective: Parkinson's disease is characterised neuropathologically by α-synuclein aggregation. Currently, there is no blood test to predict the underlying pathology or distinguish Parkinson's from atypical parkinsonian syndromes. We assessed the clinical utility of serum neuronal exosomes as biomarkers across the spectrum of Parkinson's disease, multiple system atrophy and other proteinopathies.Methods: We performed a cross-sectional study of 664 serum samples from the Oxford, Kiel and Brescia cohorts consisting of individuals with rapid eye movement sleep behavioural disorder, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, frontotemporal dementia, progressive supranuclear palsy, corticobasal syndrome and controls. Longitudinal samples were analysed from Parkinson's and control individuals. We developed poly(carboxybetaine-methacrylate) coated beads to isolate L1 cell adhesion molecule (L1CAM)-positive extracellular vesicles with characteristics of exosomes and used mass spectrometry or multiplexed electrochemiluminescence to measure exosomal proteins.Results: Mean neuron-derived exosomal α-synuclein was increased by twofold in prodromal and clinical Parkinson's disease when compared with multiple system atrophy, controls or other neurodegenerative diseases. With 314 subjects in the training group and 105 in the validation group, exosomal α-synuclein exhibited a consistent performance (AUC=0.86) in separating clinical Parkinson's disease from controls across populations. Exosomal clusterin was elevated in subjects with non-α-synuclein proteinopathies. Combined neuron-derived exosomal α-synuclein and clusterin measurement predicted Parkinson's disease from other proteinopathies with AUC=0.98 and from multiple system atrophy with AUC=0.94. Longitudinal sample analysis showed that exosomal α-synuclein remains stably elevated with Parkinson's disease progression.Conclusions: Increased α-synuclein egress in serum neuronal exosomes precedes the diagnosis of Parkinson's disease, persists with disease progression and in combination with clusterin predicts and differentiates Parkinson's disease from atypical parkinsonism. [ABSTRACT FROM AUTHOR]

Published
2020
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33. Stem cell modeling of mitochondrial parkinsonism reveals key functions of OPA1

Author

Jonikas, Mindaugas, primary, Madill, Martin, additional, Mathy, Alexandre, additional, Zekoll, Theresa, additional, Zois, Christos E., additional, Wigfield, Simon, additional, Kurzawa‐Akanbi, Marzena, additional, Browne, Cathy, additional, Sims, David, additional, Chinnery, Patrick F., additional, Cowley, Sally A., additional, and Tofaris, George K., additional

Published
2018
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35. Dopamine enhances willingness to exert effort for reward in Parkinson's disease

Author

Chong, Trevor T.-J., Bonnelle, Valerie, Manohar, Sanjay, Veromann, Kai-Riin, Muhammed, Kinan, Tofaris, George K., Hu, Michele, and Husain, Masud

Subjects
Reward, Neurology, Dopamine, Parkinson's disease, Effort, Clinical Neurology, Decision-making
Abstract

Parkinson's disease (PD) is traditionally conceptualised as a disorder of movement, but recent data suggest that motivational deficits may be more pervasive than previously thought. Here, we ask whether subclinical deficits in incentivised decision-making are present in PD and, if so, whether dopaminergic therapy ameliorates such deficits. We devised a novel paradigm in which participants decided whether they were willing to squeeze a hand-held dynamometer at varying levels of force for different magnitudes of reward. For each participant, we estimated the effort level at which the probability of accepting a reward was 50% – the effort ‘indifference point’. Patients with PD (N = 26) were tested ON and OFF their usual dopaminergic medication, and their performance compared to those of age-matched controls (N = 26). No participant was clinically apathetic as defined by the Lille Apathy Rating Scale (LARS). Our data show that, regardless of medication status, patients with PD chose to engage less effort than controls for the lowest reward. Overall, however, dopamine had a motivating effect on participants' choice behaviour – patients with PD chose to invest more effort for a given reward when they were in the ON relative to OFF dopamine state. Importantly, this effect could not be attributed to motor facilitation. We conclude that deficits in incentivised decision-making are present in PD even in the absence of a clinical syndrome of apathy when rewards are low, but that dopamine acts to eliminate motivational deficits by promoting the allocation of effort.

Published
2016

36. Identification of distinct circulating exosomes in Parkinson's disease

Author

Tomlinson, Paul R, Zheng, Ying, Fischer, Roman, Heidasch, Ronny, Gardiner, Chris, Evetts, Samuel, Hu, Michele, Wade-Martins, Richard, Turner, Martin R, Morris, John, Talbot, Kevin, Kessler, Benedikt M, and Tofaris, George K

Subjects
Research Articles
Abstract

Objective Whether circulating microvesicles convey bioactive signals in neurodegenerative diseases remains currently unknown. In this study, we investigated the biochemical composition and biological function of exosomes isolated from sera of patients with Parkinson's disease (PD). Methods Proteomic analysis was performed on microvesicle preparations from grouped samples of patients with genetic and sporadic forms of PD, amyotrophic lateral sclerosis, and healthy subjects. Nanoparticle-tracking analysis was used to assess the number and size of exosomes between patient groups. To interrogate their biological effect, microvesicles were added to primary rat cortical neurons subjected to either nutrient deprivation or sodium arsenite. Results Among 1033 proteins identified, 23 exosome-associated proteins were differentially abundant in PD, including the regulator of exosome biogenesis syntenin 1. These protein changes were detected despite similar exosome numbers across groups suggesting that they may reflect exosome subpopulations with distinct functions. Accordingly, we showed in models of neuronal stress that Parkinson's-derived microvesicles have a protective effect. Interpretation Collectively, these data suggest for the first time that immunophenotyping of circulating exosome subpopulations in PD may lead to a better understanding of the systemic response to neurodegeneration and the development of novel therapeutics.

Published
2016

37. Intact Acquisition and Short-Term Retention of Non-Motor Procedural Learning in Parkinson’s Disease

Author

Panouillères, Muriel T. N., Tofaris, George K., Brown, Peter, and Jenkinson, Ned

Subjects
Adult, Male, Physiology, education, Social Sciences, Human Learning, Learning and Memory, Elderly, Cognition, Memory, Medicine and Health Sciences, Learning, Psychology, Humans, Aged, Movement Disorders, Cognitive Psychology, Biology and Life Sciences, Retention, Psychology, Neurodegenerative Diseases, Parkinson Disease, Middle Aged, Young Adults, Neurology, Age Groups, Geriatrics, Motor Skills, People and Places, Cognitive Science, Population Groupings, Female, Physiological Processes, Sleep, Research Article, Neuroscience
Abstract

Procedural learning is a form of memory where people implicitly acquire a skill through repeated practice. People with Parkinson's disease (PD) have been found to acquire motor adaptation, a form of motor procedural learning, similarly to healthy older adults but they have deficits in long-term retention. A similar pattern of normal learning on initial exposure with a deficit in retention seen on subsequent days has also been seen in mirror-reading, a form of non-motor procedural learning. It is a well-studied fact that disrupting sleep will impair the consolidation of procedural memories. Given the prevalence of sleep disturbances in PD, the lack of retention on following days seen in these studies could simply be a side effect of this well-known symptom of PD. Because of this, we wondered whether people with PD would present with deficits in the short-term retention of a non-motor procedural learning task, when the test of retention was done the same day as the initial exposure. The aim of the present study was then to investigate acquisition and retention in the immediate short term of cognitive procedural learning using the mirror-reading task in people with PD. This task involved two conditions: one where triads of mirror-inverted words were always new that allowed assessing the learning of mirror-reading skill and another one where some of the triads were presented repeatedly during the experiment that allowed assessing the word-specific learning. People with PD both ON and OFF their normal medication were compared to healthy older adults and young adults. Participants were re-tested 50 minutes break after initial exposure to probe for short-term retention. The results of this study show that all groups of participants acquired and retained the two skills (mirror-reading and word-specific) similarly. These results suggest that neither healthy ageing nor the degeneration within the basal ganglia that occurs in PD does affect the mechanisms that underpin the acquisition of these new non-motor procedural learning skills and their short-term memories.

Published
2016

43. ER Stress and Autophagic Perturbations Lead to Elevated Extracellular α-Synuclein in GBA-N370S Parkinson's iPSC-Derived Dopamine Neurons

Author

Fernandes, Hugo J.R., primary, Hartfield, Elizabeth M., additional, Christian, Helen C., additional, Emmanoulidou, Evangelia, additional, Zheng, Ying, additional, Booth, Heather, additional, Bogetofte, Helle, additional, Lang, Charmaine, additional, Ryan, Brent J., additional, Sardi, S. Pablo, additional, Badger, Jennifer, additional, Vowles, Jane, additional, Evetts, Samuel, additional, Tofaris, George K., additional, Vekrellis, Kostas, additional, Talbot, Kevin, additional, Hu, Michele T., additional, James, William, additional, Cowley, Sally A., additional, and Wade-Martins, Richard, additional

Published
2016
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44. Heterozygous UCHL1loss-of-function variants cause a neurodegenerative disorder with spasticity, ataxia, neuropathy, and optic atrophy

Author

Park, Joohyun, Tucci, Arianna, Cipriani, Valentina, Demidov, German, Rocca, Clarissa, Senderek, Jan, Butryn, Michaela, Velic, Ana, Lam, Tanya, Galanaki, Evangelia, Cali, Elisa, Vestito, Letizia, Maroofian, Reza, Deininger, Natalie, Rautenberg, Maren, Admard, Jakob, Hahn, Gesa-Astrid, Bartels, Claudius, van Os, Nienke J.H., Horvath, Rita, Chinnery, Patrick F., Tiet, May Yung, Hewamadduma, Channa, Hadjivassiliou, Marios, Downes, Susan M., Németh, Andrea H., Tofaris, George K., Wood, Nicholas W., Hayer, Stefanie N., Bender, Friedemann, Menden, Benita, Cordts, Isabell, Klein, Katrin, Nguyen, Huu Phuc, Krauss, Joachim K., Blahak, Christian, Strom, Tim M., Sturm, Marc, van de Warrenburg, Bart, Lerche, Holger, Maček, Boris, Synofzik, Matthis, Ossowski, Stephan, Timmann, Dagmar, Wolf, Marc E., Smedley, Damian, Riess, Olaf, Schöls, Ludger, Houlden, Henry, Haack, Tobias B., and Hengel, Holger

Published
2023
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45. Identification of distinct circulating exosomes in Parkinson's disease

Author

Tomlinson, Paul R., primary, Zheng, Ying, additional, Fischer, Roman, additional, Heidasch, Ronny, additional, Gardiner, Chris, additional, Evetts, Samuel, additional, Hu, Michele, additional, Wade-Martins, Richard, additional, Turner, Martin R., additional, Morris, John, additional, Talbot, Kevin, additional, Kessler, Benedikt M., additional, and Tofaris, George K., additional

Published
2015
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46. Concentration-Normalized Electroanalytical Assaying of Exosomal Markers.

Author

Qian Li, Tofaris, George K., and Davis, Jason J.

Subjects
*ANALYTICAL chemistry periodicals, *EXOSOMES, *BIOLOGICAL tags, *SPECTROMETRY
Abstract

Exosomes are both active in mediating intracellular communication and potentially present a potent cargo of disease biomarkers to an assay. The robust evaluation of exosomal markers could lead to a paradigm shift in clinical analysis and associated care. To date, much of this has been hindered by issues of sample preparation and assay signal-to-noise. We introduce here the use of ultrasensitive electrochemical impedance spectroscopy to quantify both external (tetraspanin) and internal (syntenin) exosome-specific markers. Associated exosome detection limits are 1.9 × 105 particles mL-1 (equivalent to 320 aM or 9500 exosomes in 50 μL) for intact exosomes and 3-5 picomolar for internal exosomal syntenin levels with almost 5 decades of linear dynamic range. Sample preparation can be carried out by simple fine filtering of cell-conditioned medium prior to a non-NTA-determined (i.e., nanoparticle tracking analysis) exosome concentration analysis, lysing, and subsequent internal syntenin quantification. Such concentration-normalized dual-marker analysis can be used to define "analytical zones" in a manner which is then independent of absolute exosome concentration and sample preparation. [ABSTRACT FROM AUTHOR]

Published
2017
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48. Pathological Changes in Dopaminergic Nerve Cells of the Substantia Nigra and Olfactory Bulb in Mice Transgenic for Truncated Human α-Synuclein(1–120): Implications for Lewy Body Disorders

Author

Tofaris, George K., primary, Garcia Reitböck, Pablo, additional, Humby, Trevor, additional, Lambourne, Sarah L., additional, O’Connell, Mark, additional, Ghetti, Bernardino, additional, Gossage, Helen, additional, Emson, Piers C., additional, Wilkinson, Lawrence S., additional, Goedert, Michel, additional, and Grazia Spillantini, Maria, additional

Published
2006
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