دورية أكاديمية
Amygdala TDP-43 pathology is associated with behavioural dysfunction and ferritin accumulation in amyotrophic lateral sclerosis.
| العنوان: | Amygdala TDP-43 pathology is associated with behavioural dysfunction and ferritin accumulation in amyotrophic lateral sclerosis. |
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| المؤلفون: | Rifai OM; Centre for Discovery Brain Sciences, University of Edinburgh, UK.; Department of Neurology, Center for Motor Neuron Biology and Disease, Columbia University, New York, USA., Waldron FM; Institute of Medical Sciences, University of Aberdeen, UK., O'Shaughnessy J; Department of Chemistry, University of Edinburgh, UK., Read FL; Institute of Medical Sciences, University of Aberdeen, UK., Gilodi M; RNA System Biology Lab, Center for Human Technology, Istituto Italiano di Tecnologia, Genoa, Italy., Pastore A; The Maurice Wohl Institute, King's College London, London, UK., Shneider N; Department of Neurology, Center for Motor Neuron Biology and Disease, Columbia University, New York, USA., Tartaglia GG; RNA System Biology Lab, Center for Human Technology, Istituto Italiano di Tecnologia, Genoa, Italy., Zacco E; RNA System Biology Lab, Center for Human Technology, Istituto Italiano di Tecnologia, Genoa, Italy., Spence H; Institute of Medical Sciences, University of Aberdeen, UK., Gregory JM; Institute of Medical Sciences, University of Aberdeen, UK. |
| المصدر: | BioRxiv : the preprint server for biology [bioRxiv] 2024 Jun 01. Date of Electronic Publication: 2024 Jun 01. |
| نوع المنشور: | Journal Article; Preprint |
| اللغة: | English |
| بيانات الدورية: | Country of Publication: United States NLM ID: 101680187 Publication Model: Electronic Cited Medium: Internet NLM ISO Abbreviation: bioRxiv Subsets: PubMed not MEDLINE |
| مستخلص: | Background: Cognitive and behavioural symptoms associated with amyotrophic lateral sclerosis and frontotemporal spectrum disorders (ALSFTSD) are thought to be driven, at least in part, by the pathological accumulation of TDP-43. Methods: Here we examine post-mortem tissue from six brain regions associated with cognitive and behavioural symptoms in a cohort of 30 people with sporadic ALS (sALS), a proportion of which underwent standardized neuropsychological behavioural assessment as part of the Edinburgh Cognitive ALS Screen (ECAS). Results: Overall, the behavioural screen performed as part of the ECAS predicted accumulation of pathological phosphorylated TDP-43 (pTDP-43) with 100% specificity and 86% sensitivity in behaviour-associated brain regions. Notably, of these regions, pathology in the amygdala was the most predictive correlate of behavioural dysfunction in sALS. In the amygdala of sALS patients, we show variation in morphology, cell type predominance, and severity of pTDP-43 pathology. Further, we demonstrate that the presence and severity of intra-neuronal pTDP-43 pathology, but not astroglial pathology, or phosphorylated Tau pathology, is associated with behavioural dysfunction. Cases were also evaluated using a TDP-43 aptamer (TDP-43 APT ), which revealed that pathology was not only associated with behavioural symptoms, but also with ferritin levels, a measure of brain iron. Conclusions: Intra-neuronal pTDP-43 and cytoplasmic TDP-43 APT pathology in the amygdala is associated with behavioural symptoms in sALS. TDP-43 APT staining intensity is also associated with increased ferritin, regardless of behavioural phenotype, suggesting that ferritin increases may occur upstream of clinical manifestation, in line with early TDP-43 APT pathology, representing a potential region-specific imaging biomarker of early disease in ALS. Competing Interests: Conflicts of interest The authors declare no conflicts of interest. |
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| معلومات مُعتمدة: | United Kingdom WT_ Wellcome Trust; R01 NS127186 United States NS NINDS NIH HHS |
| فهرسة مساهمة: | Keywords: ALS; ECAS; Neuropathology; TDP-43; behaviour; cognition |
| تواريخ الأحداث: | Date Created: 20240610 Latest Revision: 20240613 |
| رمز التحديث: | 20240613 |
| مُعرف محوري في PubMed: | PMC11160765 |
| DOI: | 10.1101/2024.06.01.596819 |
| PMID: | 38854008 |
| قاعدة البيانات: | MEDLINE |
| DOI: | 10.1101/2024.06.01.596819 |
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