Abstract
White matter lesions in cerebral small vessel disease are related to ischemic injury and increase the risk of stroke and cognitive decline. Pathological changes due to cerebral small vessel disease are increasingly recognized outside of discrete lesions, but the metabolic alterations in nonlesional tissue has not been described. Aerobic glycolysis is critical to white matter myelin homeostasis and repair. In this study, we examined cerebral metabolism of glucose and oxygen as well as blood flow in individuals with and without cerebral small vessel disease using multitracer positron emission tomography. We show that glycolysis is relatively elevated in nonlesional white matter in individuals with small vessel disease relative to healthy, age-matched controls. On the other hand, in young healthy individuals, glycolysis is relatively low in areas of white matter susceptible to lesion formation. These results suggest that increased white matter glycolysis is a marker of pathology associated with small vessel disease.
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Data availability
Processed data required to generate the figures and tables are included as supplemental information and at https://github.com/matthewbrier/AGinSVD. The AMBR dataset is in the process of being made available for sharing to researchers with an appropriate Data Use Agreement, as required due to Protected Health Information, limitations in the initial consent process and regulations at the Knight Alzheimer Disease Research Center.
Code availability
Image processing toolboxes used in this study are freely available. Specific code to generate the figures and statistical tests are available at https://github.com/matthewbrier/AGinSVD.
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Acknowledgements
We are grateful to our research participants and their families for their altruism. We appreciate VG Lab members for their efforts in participant recruitment and acquiring, processing and assembling the AMBR dataset19. We also acknowledge the Neuroimaging Labs Research Center, Knight Alzheimer’s Disease Research Center, cyclotron and imaging staff for making this research possible. Funding for this research was provided by the National Institutes of Health/National Institute on Aging RF1AG073210 (A.G.V. and M.S.G.), R01AG057536 (A.G.V. and M.S.G.), R01AG053503 (A.G.V. and M.E.R.), P50AG005681 (J.C.M.), P01AG026276 (J.C.M.) and P01AG003991 (J.C.M. and T.L.S.B.). M.R.B. was supported by grants R25NS090978 and KL2TR002346 from NIH. Some of the MRI sequences were obtained from the Massachusetts General Hospital.
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M.R.B. contributed to developing the hypothesis, designed and implemented the analytic strategy, performed the analysis and statistical inferences and drafted and revised the manuscript. T.B. processed imaging data, performed initial analyses, developed image processing tools and revised the manuscript. M.E.R. conceived of the study, assisted in the design and critically revised the manuscript. J.C.M. contributed to data collection, supervised the overarching study and revised the manuscript. T.L.S.B. contributed to data collection and technical image analysis, provided image processing tools and revised the manuscript. A.G.V. designed the study, supervised data collection, curated the data, assisted with the analysis and revised the manuscript. A.Z.S. developed tools for the analysis, contributed to the design of the analytic strategy and revised the manuscript. M.S.G. conceived of the study, hypothesis and analytic approach, as well as drafted and revised the manuscript. M.R.B. and M.S.G. are responsible for the content of this manuscript.
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T.L.S.B. and M.S.G. have received sponsored research grant support from Siemens Healthineers AG. The other authors declare no competing interests.
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Nature Aging thanks Audrey (P.) Fan and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
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Supplemental Tables 1 – 4; Supplemental Figures 1 – 2
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Source Data Fig. 1
Single-subject measurements of metabolic parameters per tissue type.
Source Data Fig. 2
Single-subject measures of metabolic parameters parametric in lesion threshold; single-subject model fits of metabolic parameters in each tissue compartment.
Source Data Fig. 3
Single-subject measurements of each metabolic parameter parametric in d for each subpanel of the figure.
Source Data Fig. 4
Single-subject measurements in the WMv and WMn ROI at different fractional cutoffs.
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Brier, M.R., Blazey, T., Raichle, M.E. et al. Increased white matter glycolysis in humans with cerebral small vessel disease. Nat Aging 2, 991–999 (2022). https://doi.org/10.1038/s43587-022-00303-y
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DOI: https://doi.org/10.1038/s43587-022-00303-y
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