Increasing hub disruption parallels dementia severity in autosomal dominant Alzheimer disease.
| العنوان: | Increasing hub disruption parallels dementia severity in autosomal dominant Alzheimer disease. |
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| المؤلفون: | Tu JC; Department of Radiology, Washington University in St. Louis, St. Louis, MO, USA, 63108., Millar PR; Department of Neurology, Washington University in St. Louis, St. Louis, MO, USA, 63108., Strain JF; Department of Neurology, Washington University in St. Louis, St. Louis, MO, USA, 63108., Eck A; Department of Radiology, Washington University in St. Louis, St. Louis, MO, USA, 63108., Adeyemo B; Department of Neurology, Washington University in St. Louis, St. Louis, MO, USA, 63108., Daniels A; Department of Neurology, Washington University in St. Louis, St. Louis, MO, USA, 63108., Karch C; Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, USA, 63108., Huey ED; Department of Psychiatry and Human Behavior, Warren Alpert Medical School of Brown University, Providence, RI, 02912., McDade E; Department of Neurology, Washington University in St. Louis, St. Louis, MO, USA, 63108., Day GS; Department of Neurology, Mayo Clinic College of Medicine, Jacksonville, FL, USA, 32224., Yakushev I; Department of Nuclear Medicine, Technical University of Munich, Munich, Germany, 81675., Hassenstab J; Department of Neurology, Washington University in St. Louis, St. Louis, MO, USA, 63108., Morris J; Department of Neurology, Washington University in St. Louis, St. Louis, MO, USA, 63108., Llibre-Guerra JJ; Department of Neurology, Washington University in St. Louis, St. Louis, MO, USA, 63108., Ibanez L; Department of Neurology, Washington University in St. Louis, St. Louis, MO, USA, 63108.; Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, USA, 63108.; NeuroGenomics and Informatics Center, Washington University in St. Louis, St. Louis, MO, USA, 63108., Jucker M; Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany, 72076.; German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany, 72076., Mendez PC; Memory Center, Fleni, Argentina, C1428AQK., Bateman RJ; Department of Neurology, Washington University in St. Louis, St. Louis, MO, USA, 63108., Perrin RJ; Department of Neurology, Washington University in St. Louis, St. Louis, MO, USA, 63108.; Department of Pathology and Immunology, Washington University in St. Louis, St. Louis, MO, USA, 63108., Benzinger T; Department of Neurology, Washington University in St. Louis, St. Louis, MO, USA, 63108., Jack CR Jr; Department of Radiology, Mayo Clinic, Rochester, MN, USA 55905., Betzel R; Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN USA, 47405., Ances BM; Department of Neurology, Washington University in St. Louis, St. Louis, MO, USA, 63108., Eggebrecht AT; Department of Radiology, Washington University in St. Louis, St. Louis, MO, USA, 63108., Gordon BA; Department of Radiology, Washington University in St. Louis, St. Louis, MO, USA, 63108., Wheelock MD; Department of Radiology, Washington University in St. Louis, St. Louis, MO, USA, 63108. |
| مؤلفون مشاركون: | Dominantly Inherited Alzheimer Network |
| المصدر: | BioRxiv : the preprint server for biology [bioRxiv] 2023 Nov 01. Date of Electronic Publication: 2023 Nov 01. |
| نوع المنشور: | 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: | Hub regions in the brain, recognized for their roles in ensuring efficient information transfer, are vulnerable to pathological alterations in neurodegenerative conditions, including Alzheimer Disease (AD). Given their essential role in neural communication, disruptions to these hubs have profound implications for overall brain network integrity and functionality. Hub disruption, or targeted impairment of functional connectivity at the hubs, is recognized in AD patients. Computational models paired with evidence from animal experiments hint at a mechanistic explanation, suggesting that these hubs may be preferentially targeted in neurodegeneration, due to their high neuronal activity levels-a phenomenon termed "activity-dependent degeneration". Yet, two critical issues were unresolved. First, past research hasn't definitively shown whether hub regions face a higher likelihood of impairment (targeted attack) compared to other regions or if impairment likelihood is uniformly distributed (random attack). Second, human studies offering support for activity-dependent explanations remain scarce. We applied a refined hub disruption index to determine the presence of targeted attacks in AD. Furthermore, we explored potential evidence for activity-dependent degeneration by evaluating if hub vulnerability is better explained by global connectivity or connectivity variations across functional systems, as well as comparing its timing relative to amyloid beta deposition in the brain. Our unique cohort of participants with autosomal dominant Alzheimer Disease (ADAD) allowed us to probe into the preclinical stages of AD to determine the hub disruption timeline in relation to expected symptom emergence. Our findings reveal a hub disruption pattern in ADAD aligned with targeted attacks, detectable even in pre-clinical stages. Notably, the disruption's severity amplified alongside symptomatic progression. Moreover, since excessive local neuronal activity has been shown to increase amyloid deposition and high connectivity regions show high level of neuronal activity, our observation that hub disruption was primarily tied to regional differences in global connectivity and sequentially followed changes observed in Aβ PET cortical markers is consistent with the activity-dependent degeneration model. Intriguingly, these disruptions were discernible 8 years before the expected age of symptom onset. Taken together, our findings not only align with the targeted attack on hubs model but also suggest that activity-dependent degeneration might be the cause of hub vulnerability. This deepened understanding could be instrumental in refining diagnostic techniques and developing targeted therapeutic strategies for AD in the future. Competing Interests: Competing interests All authors report no competing interests. |
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| معلومات مُعتمدة: | P30 AG066444 United States AG NIA NIH HHS; U01 AG079850 United States AG NIA NIH HHS; K01 AG053474 United States AG NIA NIH HHS; P30 NS098577 United States NS NINDS NIH HHS; R01 MH120794 United States MH NIMH NIH HHS; K99 EB029343 United States EB NIBIB NIH HHS; S10 OD025214 United States OD NIH HHS; R01 AG062268 United States AG NIA NIH HHS; U19 AG032438 United States AG NIA NIH HHS; R00 EB029343 United States EB NIBIB NIH HHS |
| فهرسة مساهمة: | Keywords: Alzheimer disease; biomarker; functional connectivity; hubs; neurodegeneration |
| تواريخ الأحداث: | Date Created: 20231114 Latest Revision: 20240531 |
| رمز التحديث: | 20240531 |
| مُعرف محوري في PubMed: | PMC10634945 |
| DOI: | 10.1101/2023.10.29.564633 |
| PMID: | 37961586 |
| قاعدة البيانات: | MEDLINE |
| DOI: | 10.1101/2023.10.29.564633 |
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