4.7 Article

Association of Cerebrovascular and Alzheimer Disease Biomarkers With Cholinergic White Matter Degeneration in Cognitively Unimpaired Individuals

期刊

NEUROLOGY
卷 99, 期 15, 页码 E1619-E1629

出版社

LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1212/WNL.0000000000200930

关键词

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资金

  1. Swedish Research Council [2019-02075, 2013-8717, 2015-02830, 2016-02282, 2020-02014, 2021-01861, 2018-02532]
  2. Swedish Research Council for Health, Working Life and Welfare [2013-1202, AGECAP 2013-2300, 2013-2496, 2013-0475]
  3. Swedish Foundation for Strategic Research (SSF) [RB130192]
  4. Strategic Research Programme in Neuroscience at Karolinska Institutet (StratNeuro)
  5. Swedish government, ALF agreement [FoUI-954893, FoUI-962240, ALF GBG-81392, ALF GBG-771071]
  6. Swedish county councils, ALF agreement [FoUI-954893, FoUI-962240, ALF GBG-81392, ALF GBG-771071]
  7. Center for Medical Innovation (CIMED) [FoUI-954459, FoUUI-20200505]
  8. Swedish Alzheimer Foundation [AF967495, AF-939687, AF-968032]
  9. Swedish Brain Foundation [FO2020-0150, FO2021-0119, FO2022-0175]
  10. Stonhes Stiftelse
  11. Stiftelsen for Gamla Tjanarinnor
  12. Demensforbundet
  13. Neurofonden
  14. Lindhes Advokatbyra AB
  15. Eivind och Elsa K: son Sylvans Stiftelse
  16. Stiftelsen Demensfonden
  17. Stiftelsen Hjalmar Svenssons Forskningsfond
  18. Stiftelsen Wilhelm och Martina Lundgrens Vetenskapsfond
  19. Funding for Geriatric diseases at Karolinska Institutet
  20. Karolinska Institutet
  21. Fundacion Canaria Dr. Manuel Morales
  22. Czech Alzheimer Foundation
  23. Miguel Servet program [CP19/00031]
  24. Instituto de Salud Carlos III-Fondo Europeo de Desarrollo Regional (ISCIII-FEDER) [PI20/00613]
  25. Strategic Research Programme in Neuroscience at Karolinska Institutet (StratNeuro Startup Grant)
  26. Center for Medical Innovation [20200695]
  27. Gamla Tjanarinnor [2019-00803]
  28. Stonhes
  29. European Research Council [681712]
  30. Swedish State Support forClinical Research [ALFGBG-720931]
  31. Alzheimer Drug Discovery Foundation (ADDF), USA [201809-2016862]
  32. AD Strategic Fund
  33. Alzheimer's Association [ADSF-21-831376-C, ADSF-21-831381-C, ADSF-21-831377-C]
  34. Olav Thon Foundation
  35. ErlingPersson Family Foundation
  36. Hjarnfonden, Sweden [FO2019-0228]
  37. European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant [860197]
  38. UK Dementia Research Institute at UCL
  39. Alzheimerfonden [AF-842471, AF-737641, AF-939825]
  40. Swedish Research Council [2019-02075, 2021-01861, 2020-02014, 2016-02282] Funding Source: Swedish Research Council
  41. Vinnova [2016-02282] Funding Source: Vinnova

向作者/读者索取更多资源

This study aimed to determine the contribution of amyloid, tau, and cerebrovascular biomarkers to the degeneration of cholinergic white matter projections in cognitively unimpaired individuals. The results showed that WM lesion burden played a central role in the degeneration of cholinergic pathways, while levels of A beta(38) and p-tau also contributed to degeneration. These findings are important for the development of prevention programs for neurodegeneration and cognitive impairment.
Background and Objectives Several pathologic processes might contribute to the degeneration of the cholinergic system in aging. We aimed to determine the contribution of amyloid, tau, and cerebrovascular biomarkers toward the degeneration of cholinergic white matter (WM) projections in cognitively unimpaired individuals. Methods The contribution of amyloid and tau pathology was assessed through CSF levels of the A beta(42/40) ratio and phosphorylated tau (p-tau). CSF A beta(38) levels were also measured. Cerebrovascular pathology was assessed using automatic segmentations of WM lesions (WMLs) on MRI. Cholinergic WM projections (i.e., cingulum and external capsule pathways) were modeled using tractography based on diffusion tensor imaging data. Sex and APOE epsilon 4 carriership were also included in the analysis as variables of interest. Results We included 203 cognitively unimpaired individuals from the H70 Gothenburg Birth Cohort Studies (all individuals aged 70 years, 51% female). WM lesion burden was the most important contributor to the degeneration of both cholinergic pathways (increase in mean square error [IncMSE] = 98.8% in the external capsule pathway and IncMSE = 93.3% in the cingulum pathway). Levels of A beta(38) and p-tau also contributed to cholinergic WM degeneration, especially in the external capsule pathway (IncMSE = 28.4% and IncMSE = 23.4%, respectively). The A beta(42/40) ratio did not contribute notably to the models (IncMSE<3.0%). APOE epsilon 4 carriers showed poorer integrity in the cingulum pathway (IncMSE = 21.33%). Women showed poorer integrity of the external capsule pathway (IncMSE = 21.55%), which was independent of amyloid status as reflected by the nonsignificant differences in integrity when comparing amyloid-positive vs amyloid-negative women participants (T-201 = -1.55; p = 0.123). Discussion In cognitively unimpaired older individuals, WMLs play a central role in the degeneration of cholinergic pathways. Our findings highlight the importance of WM lesion burden in the elderly population, which should be considered in the development of prevention programs for neurodegeneration and cognitive impairment.

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