Brain Communications最新文献

{"title":"Inhibition of PHLDA3 expression in human SOD1 amyotrophic lateral sclerosis astrocytes protects against neurotoxicity","authors":"Kornélia Szebényi, I. Vargová, Veselina Petrova, J. Tureckova, George M. Gibbons, Monika Rehorova, Mai Abdelgawad, Alexandra Sándor, Dana Mareková, Jessica C. F. Kwok, P. Jendelová, James W Fawcett, Andras Lakatos","doi":"10.1093/braincomms/fcae244","DOIUrl":"https://doi.org/10.1093/braincomms/fcae244","url":null,"abstract":"\u0000 Pleckstrin homology-like domain family A-member 3 (PHLDA3) has recently been identified as a player in adaptive and maladaptive cellular stress pathways. The outcome of PHLDA3 signalling was shown to vary across different cell types and states. It emerges that its expression and protein level are highly increased in amyotrophic lateral sclerosis (ALS) patient-derived astrocytes. Whether it orchestrates a supportive or detrimental function remains unexplored in the context of neurodegenerative pathologies. To directly address the role of PHLDA3 in healthy and ALS astrocytes, we used overexpression and knockdown strategies. We generated cultures of primary mouse astrocytes and also human astrocytes from control and ALS patient-derived induced pluripotent stem cells harbouring the superoxide-dismutase 1 mutation. Then, we assessed astrocyte viability and the impact of their secretome on oxidative stress responses in human stem cell-derived cortical and spinal neuronal cultures. Here, we show that PHLDA3 overexpression or knockdown in control astrocytes does not significantly affect astrocyte viability or reactive oxygen species production. However, PHLDA3 knockdown in ALS astrocytes diminishes reactive oxygen species concentrations in their supernatants, indicating that PHLDA3 can facilitate stress responses in cells with altered homeostasis. In support, supernatants of PHLDA3-silenced spinal ALS and even control spinal astrocytes with a lower PHLDA3 protein content could prevent sodium arsenite-induced stress granule formation in spinal neurons. Our findings provide evidence that reducing PHLDA3 levels may transform astrocytes into a more neurosupportive state relevant to targeting non-cell autonomous ALS pathology.","PeriodicalId":504765,"journal":{"name":"Brain Communications","volume":"41 22","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141805222","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cerebral microbleeds in patients with COVID-19: is there an inevitable connection?","authors":"Yuchang Wang, Yuetao Hu, Ruichen Zhao, Qi Wang, Jiarui Xu, Jiangyuan Yuan, Shiying Dong, Mingqi Liu, Chenrui Wu, Rongcai Jiang","doi":"10.1093/braincomms/fcae236","DOIUrl":"https://doi.org/10.1093/braincomms/fcae236","url":null,"abstract":"\u0000 The COVID-19 pandemic has underscored the critical interplay between systemic infections and neurological complications, notably cerebral microbleeds (CMBs). This comprehensive review meticulously aggregates and analyzes current evidence on CMBs’ prevalence, pathophysiological underpinnings, and clinical implications within COVID-19 cohorts. Our findings reveal a pronounced correlation between CMBs and increased severity of COVID-19, emphasizing the role of direct viral effects, inflammatory responses, and coagulation disturbances. The documented association between CMBs and elevated risks of morbidity and mortality necessitates enhanced neurological surveillance in managing COVID-19 patients. Although variability in study methodologies presents challenges, the cumulative evidence substantiates CMBs as a critical illness manifestation rather than mere coincidence. This review calls for harmonization in research methodologies to refine our understanding and guide targeted interventions. Prioritizing the detection and study of neurological outcomes, such as CMBs, is imperative for bolstering pandemic response strategies and mitigating the long-term neurological impact on survivors.","PeriodicalId":504765,"journal":{"name":"Brain Communications","volume":" 11","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141822937","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Brain metabolites are associated with sleep architecture and cognitive functioning in older adults","authors":"Christina Mueller, R. Nenert, Corina Catiul, Jennifer Pilkington, Jerzy P Szaflarski, Amy W Amara","doi":"10.1093/braincomms/fcae245","DOIUrl":"https://doi.org/10.1093/braincomms/fcae245","url":null,"abstract":"\u0000 Sleep deficits are a possible risk factor for development of cognitive decline and dementia in older age. Research suggests that neuroinflammation may be a link between the two. This observational, cross-sectional study evaluated relationships between sleep architecture, neuroinflammation, and cognitive functioning in healthy older adults. Twenty-two adults aged ≥60 years underwent whole-brain Magnetic Resonance Spectroscopic Imaging (in-vivo method of visualizing increased brain temperatures as a proxy for neuroinflammation), supervised, laboratory-based polysomnography, and comprehensive neurocognitive testing. Multiple regressions were used to assess relationships between Magnetic Resonance Spectroscopic Imaging-derived brain temperature and metabolites related to inflammation (choline; myo-inositol; N-Acetylaspartate), sleep efficiency, time and % N3 sleep, and cognitive performance. Choline, myo-inositol, and N-Acetylaspartate were associated with sleep efficiency and cognitive performance. Higher choline and myo-inositol in the bilateral frontal lobes were associated with slower processing speed and lower sleep efficiency. Higher choline and myo-inositol in bilateral frontoparietal regions were associated with better cognitive performance. Higher N-Acetylaspartate around the temporoparietal junction and adjacent white matter was associated with better visuospatial function. Brain temperature was not related to cognitive or sleep outcomes. Our findings are consistent with the limited literature regarding neuroinflammation and its relationships with sleep and cognition in older age, which has implicated aging microglia and astrocytes in circadian dysregulation, impaired glymphatic clearance, and increased blood-brain barrier integrity, with downstream effects of neurodegeneration and cognitive decline. Inflammatory processes remain difficult to measure in the clinical setting, but Magnetic Resonance Spectroscopic Imaging may serve as a marker of the relationship between neuroinflammation, sleep, and cognitive decline in older adults.","PeriodicalId":504765,"journal":{"name":"Brain Communications","volume":" 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141822863","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reduction of sacsin levels in peripheral blood mononuclear cells as a diagnostic tool for spastic ataxia of Charlevoix-Saguenay","authors":"Daniele De Ritis, Laura Ferrè, Jonathan De Winter, Clémence Tremblay-Desbiens, Mathieu Blais, Maria Teresa Bassi, Nicolas Dupré, Jonathan Baets, Massimo Filippi, F. Maltecca","doi":"10.1093/braincomms/fcae243","DOIUrl":"https://doi.org/10.1093/braincomms/fcae243","url":null,"abstract":"\u0000 Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a rare neurodegenerative disease caused by biallelic variants in the SACS gene encoding for sacsin. More than 200 pathogenic variants have been identified to date, most of which are missense. It is likely that the prevalence of ARSACS is underestimated due to the lack of an efficient diagnostic tool able to validate variants of uncertain significance (VUS). We have previously shown that sacsin is almost absent in ARSACS patients’ fibroblasts regardless of the type of SACS variant, because sacsin carrying missense variants is cotranslationally degraded. In this work, we aimed to establish the pathogenicity of SACS variants by quantifying sacsin protein in blood samples, with relevant implications for ARSACS diagnosis.\u0000 We developed a protocol to assess sacsin protein levels by Western Blot using small amounts of peripheral blood mononuclear cells (PBMCs), which can be propagated in culture and cryopreserved. The study involves eight ARSACS patients (including a novel case) carrying variants of different types and positions along the SACS gene, and two parents who are carriers of heterozygous missense variants.\u0000 We show that ARSACS patients (carrying either missense or truncating variants) almost completely lacked sacsin in PBMCs. Moreover, both carriers of a SACS missense variant showed 50% reduction in sacsin protein levels compared to controls. We also describe a patient with uniparental isodisomy carrying a homozygous nonsense variant near the 3′ end of the SACS gene. This resulted in a stable sacsin protein lacking the last 202 aminoacids, probably due to escape of nonsense mediated decay of mRNA.\u0000 In conclusion, we have optimized a minimally invasive diagnostic tool for ARSACS in blood samples based on sacsin protein levels assessment. Indeed, our results provide definite evidence that sacsin carrying missense pathogenic variants undergoes cotranslational degradation. The quantitative reduction in sacsin levels in the case of missense VUS allows to define them as pathogenic variants, something which can’t be predicted bioinformatically with high certainty.","PeriodicalId":504765,"journal":{"name":"Brain Communications","volume":" 37","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141827827","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical phenotyping is key to differentiating RFC1-associated neuropathy from immune-mediated neuropathy","authors":"Sue-Faye Siow, Kishore Raj Kumar","doi":"10.1093/braincomms/fcae212","DOIUrl":"https://doi.org/10.1093/braincomms/fcae212","url":null,"abstract":"This scientific commentary refers to ‘Pathologic RFC1 repeat expansions do not contribute to the development of inflammatory neuropathies’, by Nagy et al. (https://doi.org/10.1093/braincomms/fcae163)","PeriodicalId":504765,"journal":{"name":"Brain Communications","volume":"78 23","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141338007","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Predicting conversion from mild cognitive impairment to Alzheimer’s disease: a multimodal approach","authors":"Daniel Agostinho, M. Simões, M. Castelo-Branco","doi":"10.1093/braincomms/fcae208","DOIUrl":"https://doi.org/10.1093/braincomms/fcae208","url":null,"abstract":"\u0000 Successively predicting whether mild cognitive impairment patients will progress to Alzheimer’s disease is of significant clinical relevance. This ability may provide information that can be leveraged by emerging intervention approaches and thus mitigate some of the negative effects of the disease. Neuroimaging biomarkers have gained some attention in recent years and may be useful in predicting the conversion of mild cognitive impairment to Alzheimer’s disease.\u0000 We implemented a novel multi-modal approach that allowed us to evaluate the potential of different imaging modalities, both alone and in different degrees of combinations, in predicting the conversion to Alzheimer’s disease of mild cognitive impairment patients. We applied this approach to the imaging data from the Alzheimer’s Disease Neuroimaging Initiative which is a multimodal imaging dataset comprised of MRI, Fluorodeoxyglucose-PET, Florbetapir-PET, and diffusion tensor imaging. We included a total of 480 mild cognitive impairment patients that were split into two groups: converted and stable. Imaging data were segmented into atlas-based regions of interest, from which relevant features were extracted for the different imaging modalities and used to construct machine-learning models to classify mild cognitive impairment patients into converted or stable, using each of the different imaging modalities independently. The models were then combined, using a simple weight fusion ensemble strategy, to evaluate the complementarity of different imaging modalities and their contribution to the prediction accuracy of the models.\u0000 The single-modality findings revealed that the model, utilizing features extracted from Florbetapir -PET, demonstrated the highest performance with a balanced accuracy of 83.51%. Concerning multi-modality models, not all combinations enhanced mild cognitive impairment conversion prediction. Notably, the combination of MRI with Fluorodeoxyglucose -PET emerged as the most promising, exhibiting an overall improvement in predictive capabilities, achieving a balanced accuracy of 78.43%. This indicates synergy and complementarity between the two imaging modalities in predicting mild cognitive impairment conversion.\u0000 These findings suggest that β-amyloid accumulation provides robust predictive capabilities, while the combination of multiple imaging modalities has the potential to surpass certain single-modality approaches. Exploring modality-specific biomarkers, we identified the brainstem as a sensitive biomarker for both MRI and Fluorodeoxyglucose -PET modalities, implicating its involvement in early Alzheimer's pathology. Notably, the corpus callosum and adjacent cortical regions emerged as potential biomarkers, warranting further study into their role in the early stages of Alzheimer’s disease.","PeriodicalId":504765,"journal":{"name":"Brain Communications","volume":"49 14","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141343984","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Considerations for legal, ethical, and effective practice in dementia research","authors":"Michael C B David, Martina Del Giovane, Danielle Wilson, Trevor Truman, Jonathan D Huntley, M. Suleman, Alexander Ruck Keene, Michael Parker, David J Sharp, Paresh A Malhotra","doi":"10.1093/braincomms/fcae211","DOIUrl":"https://doi.org/10.1093/braincomms/fcae211","url":null,"abstract":"\u0000 Dementia represents a potentially overwhelming health burden, both for the UK and worldwide. Addressing this fast-growing issue is a key priority for the government, health service, and the public. Advances in care including the development of efficacious disease-modifying, and eventually curative, treatments can only be achieved through effective dementia research. Specifically, research directly involving participants with dementia is essential to further understanding. However, working with cognitively impaired participants with and without capacity to consent to research presents unique ethical and legal challenges. For clinicians and scientists on the frontline of dementia research, scenarios frequently arise that pose such challenges. A lack of guidance for a consistent approach in navigating these scenarios limits researchers’ ability to proceed with confidence. This represents a threat to the rights and wishes of research participants as well as the field at large, as it may lead to studies being unnecessarily terminated or, worse, poor practice.\u0000 In this article, we take a multiprofessional approach, informed by carer input, to these issues. We review the relevant ethical and legal literature relating to the conduct of non-interventional research studies in patients with dementia. This includes a thorough recap of the Mental Capacity Act (2005), which provides a legal framework in England and Wales for conducting research with participants who lack capacity to consent. We also discuss the important, but sometimes incomplete, role of research ethics committees in guiding researchers. We then present and discuss a series of case vignettes designed to highlight areas of incomplete coverage by existing governance. These vignettes describe theoretical scenarios informed by our own real-word experiences of encountering ethical issues when conducting dementia research. They include scenarios in which participants demonstrate varying degrees of understanding of the research they are involved in and ability to communicate their wishes and feelings. Building on these vignettes we then provide a checklist for researchers to work through when presented with similar scenarios. This checklist covers the key ethical, legal, and practical considerations that we have argued for.\u0000 Taken together this article can act as a guide, previously lacking in the literature, for colleagues in the field to enable much needed ethical, legal, and effective research.","PeriodicalId":504765,"journal":{"name":"Brain Communications","volume":"18 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141341362","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impaired glymphatic system in genetic frontotemporal dementia: a GENFI study","authors":"E. Premi, Matteo Diano, Irene Mattioli, Daniele Altomare, V. Cantoni, M. Bocchetta, R. Gasparotti, E. Buratti, Marta Pengo, A. Bouzigues, L. Russell, Phoebe H. Foster, E. Ferry‐Bolder, Carolin Heller, J. V. van Swieten, L. Jiskoot, H. Seelaar, F. Moreno, R. Sánchez-Valle, Daniela Galimberti, R. Laforce, Caroline Graff, M. Masellis, M. Tartaglia, James B. Rowe, E. Finger, R. Vandenberghe, A. de Mendonça, Christopher R. Butler, Alexander Gerhard, S. Ducharme, I. Le Ber, Pietro Tiraboschi, Isabel Santana, Florence Pasquier, M. Synofzik, J. Levin, M. Otto, S. Sorbi, J. Rohrer, B. Borroni, David L. Thomas, E. Todd, C. Greaves, Jennifer Nicholas, K. Samra, R. Convery, C. Timberlake, Thomas Edward Cope, T. Rittman, A. Arighi, C. Fenoglio, E. Scarpini, G. Fumagalli, Vittoria Borracci, G. Rossi, G. Giaccone, G. Di Fede, P. Caroppo, S. Prioni, V. Redaelli, D. Tang‐Wai, E. Rogaeva, M. Castelo-Branco, Morris Freedman, Ron Keren, Sandra E. Black, S. Mitchell, C. Shoesmith, R. Bartha, R. Rademakers, J. Poos, J. Papma, ","doi":"10.1093/braincomms/fcae185","DOIUrl":"https://doi.org/10.1093/braincomms/fcae185","url":null,"abstract":"\u0000 The glymphatic system is an emerging target in neurodegenerative disorders. Here we investigated the activity of the glymphatic system in genetic Frontotemporal Dementia (FTD) with a diffusion-based technique called diffusion tensor image analysis along the perivascular space (DTI-ALPS).\u0000 We investigated 291 subjects with symptomatic or presymptomatic FTD (112 with C9orf72 expansion, 119 with GRN mutations, and 60 with MAPT mutations), and 83 non-carriers (NC, including 50 young and 33 old NC). We computed the DTI-ALPS index by calculating diffusivities in the x, y, and z axes of the plane of the lateral ventricle body. Clinical stage and blood-based markers were considered. A subset of 180 participants underwent cognitive follow-ups for a total of 640 evaluations.\u0000 The DTI-ALPS index was lower in symptomatic FTD (estimated marginal mean±standard error, 1.21±0.02) than in old NC (1.29±0.03, p=0.009) and presymptomatic mutation carriers (1.30±0.01, p<0.001). In mutation carriers, lower DTI-ALPS was associated with worse disease severity (β=-1.16, p<0.001), and a trend towards a significant association between lower DTI-ALPS and higher plasma neurofilament light chain was reported (β=-0.28, p=0.063). Analysis of longitudinal data demonstrated that worsening of disease severity was faster in patients with low DTI-ALPS at baseline than in those with average (p=0.009) or high (p=0.006) DTI-ALPS index.\u0000 Using a non-invasive imaging approach as a proxy for glymphatic system function, we demonstrated glymphatic system abnormalities in the symptomatic stages of genetic FTD. Such measures of the glymphatic system may elucidate pathophysiological processes in human FTD and facilitate early phase trials of genetic FTD.","PeriodicalId":504765,"journal":{"name":"Brain Communications","volume":"12 19","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141340874","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Potential biomarkers for multiple sclerosis stage from targeted proteomics and microRNA sequencing","authors":"Ineke L. Tan, R. Modderman, Anna Stachurska, Rodrigo Almeida, Riemer de Vries, Dorothea J Heersema, R. Gacesa, C. Wijmenga, Iris H Jonkers, Jan F Meilof, S. Withoff","doi":"10.1093/braincomms/fcae209","DOIUrl":"https://doi.org/10.1093/braincomms/fcae209","url":null,"abstract":"\u0000 Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system. There is a need for new circulating biomarkers for multiple sclerosis, in particular markers that differentiate MS subtypes (relapsing-remitting, secondary progressive and primary progressive MS), as this can help in making treatment decisions. In this study, we explore two classes of potential MS biomarkers – proteins and microRNAs – circulating in CSF and serum.\u0000 Targeted medium-throughput proteomics (92 proteins) and microRNA sequencing were performed on serum samples collected in a cross-sectional case–control cohort (cohort I, controls n=30, MS n=75) and a prospective MS cohort (cohort II, n=93). For cohort I, we also made these measurements in paired CSF samples.\u0000 In the cohort I CSF, we observed differences between MS and controls for 13 proteins, including some previously described to be markers for MS (e.g. CD27, C-X-C motif chemokine 13 (CXCL13), interleukin-7 (IL7). No microRNAs were significantly differentially expressed between MS and controls in CSF. In serum, 10 proteins (including angiopoietin-1 receptor (TIE2)) and 16 microRNAs were significantly different between relapsing-remitting MS and secondary progressive MS after performing a meta-analysis combining both cohorts. In the prospective part of the study, participants with relapsing-remitting MS were followed for around 3 years, during which time 12 participants converted to secondary progressive MS. In these longitudinally collected serum samples, we observed a peak in granzyme B, A and H proteins around the time of conversion. Single-sample enrichment analysis of serum microRNA profiles revealed that the peak in granzyme B levels around conversion coincides with enrichment for microRNAs that are enriched in CD4+, CD8+ and natural killer cells (e.g. miRNA-150).\u0000 We identified several proteins and microRNAs in serum that represent potential biomarkers for relapsing-remitting and secondary progressive MS. Conversion to secondary progressive disease is marked by a peak in granzyme B levels and enrichment for immune-related microRNAs. This indicates that specific immune cell–driven processes may contribute to the conversion of relapsing-remitting MS to secondary progressive MS.","PeriodicalId":504765,"journal":{"name":"Brain Communications","volume":"39 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141345086","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Disruption in functional networks mediated tau spreading in Alzheimer’s disease","authors":"F. Nabizadeh","doi":"10.1093/braincomms/fcae198","DOIUrl":"https://doi.org/10.1093/braincomms/fcae198","url":null,"abstract":"\u0000 Alzheimer’s disease may be conceptualized as a “disconnection syndrome,” characterized by the breakdown of neural connectivity within the brain as a result of amyloid-beta plaques, tau neurofibrillary tangles, and other factors leading to progressive degeneration and shrinkage of neurons, along with synaptic dysfunction. It has been suggested that misfolded spread through functional connections (known as ‘prion-like properties of tau). However, the local effect of tau spreading on the synaptic function and communication between regions is not well understood. I aimed to investigate how the spreading of tau aggregates through connections can locally influence functional connectivity. In total, the imaging data of 211 participants including, 117 amyloid-beta-negative non-demented and 94 amyloid-beta-positive non-demented participants were recruited from Alzheimer's disease Neuroimaging Initiative (ADNI). Furthermore, normative resting-state functional MRI connectomes were used to model tau spreading through functional connections, and functional MRI of the included participants was used to determine the effect of tau spreading on functional connectivity. I found that lower functional connectivity to tau epicenters is associated with tau spreading through functional connections in both amyloid-beta-negative and amyloid-beta-positive participants. Also, amyloid-beta-PET in tau epicenters mediated the association of tau spreading and functional connectivity to epicenters suggesting a partial mediating effect of amyloid-beta deposition in tau epicenters on the local effect of tau spreading on functional connectivity. My findings provide strong support for the notion that tau spreading through connection is locally associated with disrupted functional connectivity between tau epicenter and non-epicenter regions independent of amyloid-beta pathology. Also, I defined several groups based on the relationship between tau spreading and functional disconnection which provides quantitative assessment to investigate susceptibility or resilience to functional disconnection related to tau spreading. I showed that amyloid-beta, other copathologies, and the Apolipoprotein E epsilon 4 (APOE ε4) allele can be a leading factor towards vulnerability to tau relative functional disconnection.","PeriodicalId":504765,"journal":{"name":"Brain Communications","volume":"67 8","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141346422","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}