761 research outputs found
The acidic cluster of the CK2 site of the cation-dependent mannose 6-phosphate receptor (CD-MPR) but not its phosphorylation is required for GGA1 and AP-1 binding
No full textLysosomal biogenesis depends on proper transport of lysosomal enzymes by the cation-dependent mannose 6-phosphate receptor (CD-MPR) from the trans-Golgi network (TGN) to endosomes. Trafficking of the CD-MPR is mediated by sorting signals in its cytoplasmic tail. GGA1 (Golgi-localizing, gamma-ear-containing, ARF-binding protein-1) binds to CD-MPR in the TGN and targets the receptor to clathrin-coated pits for transport from the TGN to endosomes. The motif of the CD-MPR that interacts with GGA1 was shown to be (DXXLL65)-D-61. Reports on increased affinity of cargo, when phosphorylated by casein kinase 2 (CK2), to GGAs focused our interest on the effect of the CD-MPR CK2 site on binding to GGA1. Here we demonstrate that Glu(58) and Glu(59) of the CK2 site are essential for high affinity GGA1 binding in vitro, whereas the phosphorylation of Ser(57) of the CD-MPR has no influence on receptor binding to GGA1. Furthermore, the in vivo interaction between GGA1 and CD-MPR was abolished only when all residues involved in GGA1 binding were mutated, namely, Glu(58), Glu(59), Asp(61), Leu(64), and Leu(65). In contrast, the binding of adaptor protein-1 (AP-1) to CD-MPR required all the glutamates surrounding the phosphorylation site, namely, Glu(55), Glu(56), Glu(58), and Glu(59), but like GGA1 binding, was independent of the phosphorylation of Ser(57). The binding affinity of GGA1 to the CD-MPR was found to be 2.4-fold higher than that of AP-1. This could regulate the binding of the two proteins to the partly overlapping sorting signals, allowing AP-1 binding to the CD-MPR only when GGA1 is released upon autoinhibition by phosphorylation
The problematic syndrome of right temporal lobe atrophy: Unweaving the phenotypic rainbow
No full textChristopher R. S. Belder, Anthipa Chokesuwattanaskul, Charles R. Marshall, Chris J. D. Hardy, Jonathan D. Rohrer, and Jason D. Warre
Exome sequencing reveals a novel partial deletion in the progranulin gene causing primary progressive aphasia.
No full textAbstract not availableJonathan D Rohrer, Jonathan Beck, Vincent Plagnol, Elizabeth Gordon, Tammaryn Lashley, Tamas Revesz, John C Janssen, Nick C Fox, Jason D Warren, Martin N Rossor, Simon Mead, Jonathan M Schot
Correction to: Uncovering spatiotemporal patterns of atrophy in progressive supranuclear palsy using unsupervised machine learning
No full textThis is a correction to: William J Scotton, Cameron Shand, Emily Todd, Martina Bocchetta, David M Cash, Lawren VandeVrede, Hilary Heuer, PROSPECT Consortium, 4RTNI Consortium, Alexandra L Young, Neil Oxtoby, Daniel C Alexander, James B Rowe, Huw R Morris, Adam L Boxer, Jonathan D Rohrer, Peter A Wijeratne, Uncovering spatiotemporal patterns of atrophy in progressive supranuclear palsy using unsupervised machine learning, Brain Communications, Volume 5, Issue 2, 2023, https://doi.org/10.1093/braincomms/fcad04
Dysphagia in primary progressive aphasia: Clinical predictors and neuroanatomical basis
No full textBackground and purpose: Dysphagia is an important feature of neurodegenerative diseases and potentially life-threatening in primary progressive aphasia (PPA) but remains poorly characterized in these syndromes. We hypothesized that dysphagia would be more prevalent in nonfluent/agrammatic variant (nfv)PPA than other PPA syndromes, predicted by accompanying motor features, and associated with atrophy affecting regions implicated in swallowing control. Methods: In a retrospective case–control study at our tertiary referral centre, we recruited 56 patients with PPA (21 nfvPPA, 22 semantic variant [sv]PPA, 13 logopenic variant [lv]PPA). Using a pro forma based on caregiver surveys and clinical records, we documented dysphagia (present/absent) and associated, potentially predictive clinical, cognitive, and behavioural features. These were used to train a machine learning model. Patients' brain magnetic resonance imaging scans were assessed using voxel-based morphometry and region-of-interest analyses comparing differential atrophy profiles associated with dysphagia presence/absence. Results: Dysphagia was significantly more prevalent in nfvPPA (43% vs. 5% svPPA and no lvPPA). The machine learning model revealed a hierarchy of features predicting dysphagia in the nfvPPA group, with excellent classification accuracy (90.5%, 95% confidence interval = 77.9–100); the strongest predictor was orofacial apraxia, followed by older age, parkinsonism, more severe behavioural disturbance, and more severe cognitive impairment. Significant grey matter atrophy correlates of dysphagia in nfvPPA were identified in left middle frontal, right superior frontal, and right supramarginal gyri and right caudate. Conclusions: Dysphagia is a common feature of nfvPPA, linked to underlying corticosubcortical network dysfunction. Clinicians should anticipate this symptom particularly in the context of other motor features and more severe disease
Primary progressive aphasia: six questions in search of an answer
No full textHere, we review recent progress in the diagnosis and management of primary progressive aphasia—the language-led dementias. We pose six key unanswered questions that challenge current assumptions and highlight the unresolved difficulties that surround these diseases. How many syndromes of primary progressive aphasia are there—and is syndromic diagnosis even useful? Are these truly ‘language-led’ dementias? How can we diagnose (and track) primary progressive aphasia better? Can brain pathology be predicted in these diseases? What is their core pathophysiology? In addition, how can primary progressive aphasia best be treated? We propose that pathophysiological mechanisms linking proteinopathies to phenotypes may help resolve the clinical complexity of primary progressive aphasia, and may suggest novel diagnostic tools and markers and guide the deployment of effective therapies
A systematic review of the quantitative markers of speech and language of the frontotemporal degeneration spectrum and their potential for cross-linguistic implementation
No full textFrontotemporal dementia (FTD) is a neurodegenerative disease spectrum with an urgent need for reliable biomarkers for early diagnosis and monitoring. Speech and language changes occur in the early stages of FTD and offer a potential non-invasive, early, and accessible diagnostic tool. The use of speech and language markers in this disease spectrum is limited by the fact that most studies investigate English-speaking patients. This systematic review examines the literature on psychoacoustic and linguistic features of speech that occur across the FTD spectrum across as many different languages as possible. 76 papers were identified that investigate psychoacoustic and linguistic markers in discursive speech. 75 % of these papers studied English-speaking patients. The most generalizable features found across different languages, are speech rate, articulation rate, pause frequency, total pause duration, noun-verb ratio, and total number of nouns. While there are clear interlinguistic differences across patient groups, the results show promise for implementation of cross-linguistic markers of speech and language across the FTD spectrum particularly for psychoacoustic features.</p
Genetic testing in dementia
No full textFirst published September 17, 2024.There is growing public awareness and concern regarding dementia risk. In addition, genetic testing is increasingly accessible and is at the point of being integrated into routine clinical practice. As a result, there is a pressing need for treating clinicians to have the appropriate knowledge base to request and consent for diagnostic genetic testing in cognitive clinics. We outline our approach to genetic testing in patients with Alzheimer's disease, frontotemporal dementia, dementia with Lewy bodies and vascular cognitive impairment. We discuss when to consider testing, the consenting process, and the interpretation and communication of genetic test results.Antoinette O'Connor, Natalie S Ryan, Christopher R S Belder, David S Lynch, Nayana Lahiri, Henry Houlden, Jonathan D Rohrer, Nick C Fox, Sean O'Dow
Structural brain imaging in frontotemporal dementia
No full textAbstractFrontotemporal dementia (FTD) is the second commonest young-onset neurodegenerative dementia. The canonical clinical syndromes are a behavioural variant (bvFTD) and two language variants (progressive nonfluent aphasia, PNFA, and semantic dementia, SD) although there is overlap with motor neurone disease and the atypical parkinsonian disorders corticobasal syndrome (CBS) and progressive supranuclear palsy syndrome (PSPS). Characteristic patterns of atrophy or hypometabolism are described in each of the variants but in reality imaging studies are rather heterogeneous. This review attempts to address four key questions in the neuroimaging of FTD: 1) what are the early imaging features of the different FTD syndromes (and how do these change as the disease progresses); 2) what do studies of presymptomatic genetic cases of FTD tell us about the very early stages of the disease; 3) can neuroimaging help to differentiate the different FTD syndromes; and 4) can neuroimaging help to differentiate FTD from other neurodegenerative diseases? This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease
Corrigendum to “Dissemination in time and space in presymptomatic granulin mutation carriers: A spatial chronnectome study” [Neurobiology of Aging Volume 108, December 2021, Pages 155–167]
No full textRefers to
Enrico Premi, Marcello Giunta, Armin Iraji, Srinivas Rachakonda, Vince D. Calhoun, Stefano Gazzina, Alberto Benussi, Roberto Gasparotti, Silvana Archetti, Martina Bocchetta, Dave Cash, Emily Todd, Georgia Peakman, Rhian Convery, John C. van Swieten, Lize Jiskoot, Raquel Sanchez-Valle, Fermin Moreno, Robert Laforce, Caroline Graff, Matthis Synofzik, Daniela Galimberti, James B. Rowe, Mario Masellis, Carmela Tartaglia, Elizabeth Finger, Rik Vandenberghe, Alexandre de Mendonça, Fabrizio Tagliavini, Chris R. Butler, Isabel Santana, Alexander Gerhard, Isabelle Le Ber, Florence Pasquier, Simon Ducharme, Johannes Levin, Adrian Danek, Sandro Sorbi, Markus Otto, Jonathan D. Rohrer, Barbara Borroni
Dissemination in time and space in presymptomatic granulin mutation carriers: a GENFI spatial chronnectome study. Neurobiology of Aging, Volume 108, December 2021, Pages 155-167 DOI of original article: 10.1016/j.neurobiolaging.2021.09.001.© 2022 Elsevier Inc. The authors regret that the GENFI authors were listed at the end of the article in the Appendix. The GENFI authors are also part of co-authors. The updated author list is below. The authors would like to apologise for any inconvenience caused
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