Abstract
Subjective cognitive decline (SCD)-related worries are indicative of an increased risk for developing Alzheimer’s disease (AD) dementia. However, the influence of SCD-related worries on the relationship between amyloid and gray matter (GM) atrophy remains unknown. A total of 93 SCD participants underwent 18F-florbetapir PET and T1-weighted MRI scans. SCD individuals were classified into amyloid-positive or amyloid-negative groups based on global amyloid uptake. Three-step statistical analyses were performed: (1) partial correlation analysis was conducted to determine whether global amyloid relates to GM volume in amyloid-positive and amyloid-negative groups; (2) linear regression analysis was conducted to determine whether the interaction term (worries × global amyloid) predicts GM volume; and (3) post hoc subgroup linear regression analysis was conducted to determine the association between amyloid and GM volume in the subgroups with and without worries. Age, sex, education and total intracranial volume were adjusted in all models. We found a negative relationship between global amyloid load and GM volume in the right hemisphere (r = 0.441, p = 0.012) and right temporal cortex (r = 0.506, p = 0.003) in the amyloid-positive group. Moreover, in the amyloid-positive group, a significant worries × amyloid interaction effect on GM volume was found in the bilateral hemisphere (right: pinteraction=0.037; left: pinteraction=0.036), left temporal cortex (pinteraction=0.044) and bilateral frontal cortex (right: pinteraction=0.010; left: pinteraction=0.011). Subsequent post hoc analysis revealed a significant amyloid-GM association only in the subgroup with worries but not in the subgroup without worries. In preclinical AD cases, SCD-related worries may occur as a symptom in those cases where amyloid affects GM to a greater extent and may thus represent a high-risk population for future cognitive decline.
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References
Becker, J. A., Hedden, T., Carmasin, J., Maye, J., Rentz, D. M., Putcha, D., & Johnson, K. A. (2011). Amyloid-β associated cortical thinning in clinically normal elderly. Annals of Neurology, 69(6), 1032–1042. https://doi.org/10.1002/ana.22333
Benjamini, Y., & Hochberg, Y. (1995). Controlling the false discovery rate - A practical and powerful approach to multiple testing. Journal of the Royal Statistical Society, Series B, 57, 289–300. https://doi.org/10.2307/2346101
Bennett, D., Schneider, J., Wilson, R., Bienias, J., & Arnold, S. (2004). Neurofibrillary tangles mediate the association of amyloid load with clinical Alzheimer disease and level of cognitive function. Archives of Neurology, 61(3), 378–384. https://doi.org/10.1001/archneur.61.3.378
Bourgeat, P., Chételat, G., Villemagne, V., Fripp, J., Raniga, P., Pike, K., & Salvado, O. (2010). Beta-amyloid burden in the temporal neocortex is related to hippocampal atrophy in elderly subjects without dementia. Neurology, 74(2), 121–127. https://doi.org/10.1212/WNL.0b013e3181c918b5
Caeyenberghs, K., & Leemans, A. (2014). Hemispheric lateralization of topological organization in structural brain networks. Human Brain Mapping, 35(9), 4944–4957. https://doi.org/10.1002/hbm.22524
Chabrier, M. A., Blurton-Jones, M., Agazaryan, A. A., Nerhus, J. L., Martinez-Coria, H., & LaFerla, F. M. (2012). Soluble abeta promotes wild-type tau pathology in vivo. The Journal of Neuroscience, 32(48), 17345–17350. https://doi.org/10.1523/JNEUROSCI.0172-12.2012
Chen, K., Roontiva, A., Thiyyagura, P., Lee, W., Liu, X., Ayutyanont, N., & Reiman, E. M. (2015). Improved power for characterizing longitudinal amyloid-PET changes and evaluating amyloid-modifying treatments with a cerebral white matter reference region. Journal of Nuclear Medicine, 56(4), 560–566. https://doi.org/10.2967/jnumed.114.149732
Chen, K., Xu, Y., Chu, A., Ding, D., Liang, X., Nasreddine, Z., & Guo, Q. (2016). Validation of the Chinese version of Montreal Cognitive Assessment Basic for screening mild cognitive impairment. Journal of the American Geriatrics Society, 64(12), e285–e290. https://doi.org/10.1111/jgs.14530
Chetelat, G., Villemagne, V. L., Bourgeat, P., Pike, K. E., Jones, G., Ames, D., & Rowe, C. C. (2010). Relationship between atrophy and beta-amyloid deposition in Alzheimer disease. Annals of Neurology, 67(3), 317–324. https://doi.org/10.1002/ana.21955
Dore, V., Villemagne, V. L., Bourgeat, P., Fripp, J., Acosta, O., Chetelat, G., & Rowe, C. C. (2013). Cross-sectional and longitudinal analysis of the relationship between Abeta deposition, cortical thickness, and memory in cognitively unimpaired individuals and in Alzheimer disease. JAMA Neurology, 70(7), 903–911. https://doi.org/10.1001/jamaneurol.2013.1062
Ebenau, J., Verfaillie, S., van den Bosch, K., Timmers, T., Wesselman, L., van Leeuwenstijn, M., & van Berckel, B. (2020). Grey zone amyloid burden affects memory function: the SCIENCe project. European Journal of Nuclear Medicine and Molecular Imaging, 48(3), 747–756. https://doi.org/10.1007/s00259-020-05012-5
Fagan, A. M., Head, D., Shah, A. R., Marcus, D., Mintun, M., Morris, J. C., & Holtzman, D. M. (2009). Decreased cerebrospinal fluid Abeta(42) correlates with brain atrophy in cognitively normal elderly. Annals of Neurology, 65(2), 176–183. https://doi.org/10.1002/ana.21559
Gaubert, S., Raimondo, F., Houot, M., Corsi, M. C., Naccache, L., Sitt, D., & Epelbaum, J. (2019). EEG evidence of compensatory mechanisms in preclinical Alzheimer’s disease. Brain, 142(7), 2096–2112. https://doi.org/10.1093/brain/awz150
Glodzik-Sobanska, L., Reisberg, B., De Santi, S., Babb, J. S., Pirraglia, E., Rich, K. E., & de Leon, M. J. (2007). Subjective memory complaints: presence, severity and future outcome in normal older subjects. Dementia and Geriatric Cognitive Disorders, 24(3), 177–184. https://doi.org/10.1159/000105604
Grothe, M., Ewers, M., Krause, B., Heinsen, H., & Teipel, S. (2014). Basal forebrain atrophy and cortical amyloid deposition in nondemented elderly subjects. Alzheimer’s & Sementia: the Journal of the Alzheimer’s Association, 10(0), S344–S353. https://doi.org/10.1016/j.jalz.2013.09.011
Jack, C. R., Bennett, D. A., Blennow, K., Carrillo, M. C., Dunn, B., Haeberlein, S. B., & Silverberg, N. (2018). NIA-AA Research Framework: Toward a biological definition of Alzheimer’s disease. Alzheimer’s & Dementia: the Journal of the Alzheimer’s Association, 14(4), 535–562. https://doi.org/10.1016/j.jalz.2018.02.018
Jack, C. R., Knopman, D. S., Jagust, W. J., Petersen, R. C., Weiner, M. W., Aisen, P. S., & Trojanowski, J. Q. (2013). Tracking pathophysiological processes in Alzheimer’s disease: an updated hypothetical model of dynamic biomarkers. The Lancet Neurology, 12(2), 207–216. https://doi.org/10.1016/s1474-4422(12)70291-0
Jessen, F., Amariglio, R. E., van Boxtel, M., Breteler, M., Ceccaldi, M., Chetelat, G., & Wagner, M. (2014). A conceptual framework for research on subjective cognitive decline in preclinical Alzheimer’s disease. Alzheimer’s & Dementia: the Journal of the Alzheimer’s Association, 10(6), 844–852. https://doi.org/10.1016/j.jalz.2014.01.001
Jessen, F., Wolfsgruber, S., Wiese, B., Bickel, H., Mösch, E., Kaduszkiewicz, H., & Wagner, M. (2014). AD dementia risk in late MCI, in early MCI, and in subjective memory impairment. Alzheimer’s & Dementia: the Journal of the Alzheimer’s Association, 10(1), 76–83. https://doi.org/10.1016/j.jalz.2012.09.017
Li, X., Wang, X., Su, L., Hu, X., & Han, Y. (2019). Sino Longitudinal Study on Cognitive Decline (SILCODE): protocol for a Chinese longitudinal observational study to develop risk prediction models of conversion to mild cognitive impairment in individuals with subjective cognitive decline. British Medical Journal Open, 9(7), e028188. https://doi.org/10.1136/bmjopen-2018-028188
Luders, E., Narr, K. L., Thompson, P. M., Rex, D. E., Jancke, L., & Toga, A. W. (2006). Hemispheric asymmetries in cortical thickness. Cerebral Cortex, 16(8), 1232–1238. https://doi.org/10.1093/cercor/bhj064
Martikainen, I. K., Kemppainen, N., Johansson, J., Teuho, J., Helin, S., Liu, Y., & Rinne, J. O. (2019). Brain β-amyloid and atrophy in individuals at increased risk of cognitive decline. American Journal of Neuroradiology, 40(1), 80–85. https://doi.org/10.3174/ajnr.A5891
Miebach, L., Wolfsgruber, S., Polcher, A., Peters, O., Menne, F., Luther, K., & Wagner, M. (2019). Which features of subjective cognitive decline are related to amyloid pathology? Findings from the DELCODE study. Alzheimer’s Research & Therapy, 11(1), 66. https://doi.org/10.1186/s13195-019-0515-y
Minkova, L., Habich, A., Peter, J., Kaller, C., Eickhoff, S., & Klöppel, S. (2017). Gray matter asymmetries in aging and neurodegeneration: A review and meta-analysis. Human brain mapping, 38(12), 5890–5904. https://doi.org/10.1002/hbm.23772
Mormino, E. C., Kluth, J. T., Madison, C. M., Rabinovici, G. D., Baker, S. L., Miller, B. L., & Jagust, W. J. (2008). Episodic memory loss is related to hippocampal-mediated -amyloid deposition in elderly subjects. Brain, 132(5), 1310–1323. https://doi.org/10.1093/brain/awn320
Sacher, C., Blume, T., Beyer, L., Biechele, G., Sauerbeck, J., Eckenweber, F., & Brendel, M. (2020). Asymmetry of fibrillar plaque burden in amyloid mouse models. Journal of Nuclear Medicine, 61(12), 1825–1831. https://doi.org/10.2967/jnumed.120.242750
Sannemann, L., Schild, A. K., Altenstein, S., Bartels, C., Brosseron, F., Buerger, K., & Group, D. S. (2020). Neuropsychiatric symptoms in at-risk groups for AD dementia and their association with worry and AD biomarkers-results from the DELCODE study. Alzheimer’s Research & Therapy, 12(1), 131. https://doi.org/10.1186/s13195-020-00701-7
Slot, R. E. R., Sikkes, S. A. M., Berkhof, J., Brodaty, H., Buckley, R., Cavedo, E., & van der Flier, W. M. (2019). Subjective cognitive decline and rates of incident Alzheimer’s disease and non-Alzheimer’s disease dementia. Alzheimer’s & Dementia: the Journal of the Alzheimer’s Association, 15(3), 465–476. https://doi.org/10.1016/j.jalz.2018.10.003
Southekal, S., Devous, M. D., Kennedy, S., Navitsky, I., Lu, M., Joshi, M., & Mintun, A. D. (2018). Flortaucipir F 18 quantitation using parametric estimation of reference signal intensity. The Journal of Nuclear Medicine, 59(6), 944–951. https://doi.org/10.2967/jnumed.117.200006
Sun, Y., Wang, X., Wang, Y., Dong, H., Lu, J., Scheininger, T., & Han, Y. (2019). Anxiety correlates with cortical surface area in subjective cognitive decline: APOE epsilon4 carriers versus APOE epsilon4 non-carriers. Alzheimer‘s Research & Therapy, 11(1), 50. https://doi.org/10.1186/s13195-019-0505-0
Swinford, C. G., Risacher, S. L., Charil, A., Schwarz, A. J., & Saykin, A. J. (2018). Memory concerns in the early Alzheimer’s disease prodrome: Regional association with tau deposition. Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring, 10, 322–331. https://doi.org/10.1016/j.dadm.2018.03.001
Teipel, S. J., Cavedo, E., Weschke, S., Grothe, M. J., Rojkova, K., & Fontaine, G. de(2017). Schotten Michel, T. Cortical amyloid accumulation is associated with alterations of structural integrity in older people with subjective memory complaints. Neurobiology of Aging, 57, 143–152. https://doi.org/10.1016/j.neurobiolaging.2017.05.016
Ten Kate, M., Visser, P. J., Bakardjian, H., Barkhof, F., Sikkes, S. A. M., van der Flier, W. M., & Tijms, B. M. (2018). Gray matter network disruptions and regional amyloid beta in cognitively normal adults. Frontiers in Aging Neuroscience, 10, 67. https://doi.org/10.3389/fnagi.2018.00067
van Harten, A. C., Mielke, M. M., Swenson-Dravis, D. M., Hagen, C. E., Edwards, K. K., Roberts, R. O., & Petersen, R. C. (2018). Subjective cognitive decline and risk of MCI. Neurology, 91(4), e300–e312. https://doi.org/10.1212/wnl.0000000000005863
Verfaillie, S. C. J., Timmers, T., Slot, R. E. R., van der Weijden, C. W. J., Wesselman, L. M. P., Prins, N. D., & van der Flier, W. M. (2019). Amyloid-β load is related to worries, but not to severity of cognitive complaints in individuals with subjective cognitive decline: The SCIENCe project. Frontiers in Aging Neuroscience, 11, 7. https://doi.org/10.3389/fnagi.2019.00007
Villemagne, V. L., Burnham, S., Bourgeat, P., Brown, B., Ellis, K. A., Salvado, O., & Masters, C. L. (2013). Amyloid β deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer’s disease: a prospective cohort study. The Lancet Neurology, 12(4), 357–367. https://doi.org/10.1016/s1474-4422(13)70044-9
Wang, M., Yan, Z., Zhang, H., Lu, J., Li, L., & Yu, J. Alzheimer’s Disease Neuroimaging, I(2021). Parametric estimation of reference signal intensity in the quantification of amyloid-beta deposition: an (18)F-AV-45 study. Quantitative Imaging in Medicine and Surgery, 11(1), 249–263. https://doi.org/10.21037/qims-20-110
Wang, X., Huang, W., Su, L., Xing, Y., Jessen, F., Sun, Y., & Han, Y. (2020). Neuroimaging advances regarding subjective cognitive decline in preclinical Alzheimer’s disease. Molecular Neurodegeneration, 15(1), 55. https://doi.org/10.1186/s13024-020-00395-3
Wolfsgruber, S., Kleineidam, L., Wagner, M., Mösch, E., Bickel, H., Lϋhmann, D., & Jessen, F. (2016). Differential risk of incident alzheimer’s disease dementia in stable versus unstable patterns of subjective cognitive decline. Journal of Alzheimer’s Disease, 54(3), 1135–1146. https://doi.org/10.3233/jad-160407
Yue, L., Wang, T., Wang, J., Li, G., Wang, J., Li, X., & Xiao, S. (2018). Asymmetry of hippocampus and amygdala defect in subjective cognitive decline among the community dwelling chinese. Frontiers in Psychiatry, 9, 226. https://doi.org/10.3389/fpsyt.2018.00226
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This article was supported by National Natural Science Foundation of China (Grant 61633018, 82020108013, 82001773).
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Xiaoqi Wang, Xiaoni Wang and Ying Han conceived and designed the manuscript. Xiaoqi Wang was responsible for searching literature, statistical analysis and drafting the manuscript. Min Wang was responsible for imaging data analysis. Xiaoni Wang, Feifan Zhou, Jiehui Jiang and Hesheng Liu made contributions to critical revisions for important intellectual content. Xiaoni Wang, Jiehui Jiang, and Ying Han revised and finalized the manuscript. All authors read and approved the final manuscript.
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Wang, X., Wang, M., Wang, X. et al. Subjective cognitive decline-related worries modulate the relationship between global amyloid load and gray matter volume in preclinical Alzheimer’s disease. Brain Imaging and Behavior 16, 1088–1097 (2022). https://doi.org/10.1007/s11682-021-00558-w
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DOI: https://doi.org/10.1007/s11682-021-00558-w