Brain Atrophy and White Matter Damage Linked to Peripheral Bioenergetic Deficits in the Neurodegenerative Disease FXTAS
Abstract
:1. Introduction
2. Results
2.1. Demographic Characteristics of Participants Included in This Study
2.2. Smaller Brain Volume in Premutation Carriers Compared to Non-Carriers, and Higher WMHV in Carriers with FXTAS Stages ≥ 2
2.3. Lower Overall Oxygen-Linked ATP Production Fueled by Succinate in Premutation PBMCs but Higher with Glycerophosphate as Substrate in Carriers with FXTAS Stages ≥ 2
2.4. Age-Dependent Negative Correlation between WMHV and Oxygen-Linked ATP Production, and Positive Correlation between Brain Volume and ATP Production and Mitochondrial Mass in the Premutation Carriers
3. Discussion
4. Materials and Methods
4.1. Research Participants
4.2. PBMCs Preparation
4.3. Mitochondrial Outcomes
4.4. MRI Acquisition and Processing
4.5. Statistical Analysis
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Measures | N | Age | PFX− vs. Controls | PFX+ vs. Controls | PFX+ vs. PFX− | ||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
β (SD) | P | FDR | β ** (SD) | P | FDR | β ** (SD) | P | FDR | β ** (SD) | P | FDR | ||
MRI | |||||||||||||
WMHV (log) | 96 | 0.050 (0.011) | <0.001 | <0.001 | 0.005 (0.45) | 0.99 | 0.99 | 1.54 (0.52) | 0.004 | 0.007 | 1.53 (0.36) | <0.001 | <0.001 |
BV (ml) | 96 | −3.18 (0.62) | <0.001 | <0.001 | −52.2 (24.4) | 0.035 | 0.046 | −86.8 (28.6) | 0.003 | 0.007 | −34.7 (19.6) | 0.08 | 0.09 |
Mitochondria | |||||||||||||
CS * | 103 | −0.026 (0.006) | <0.001 | <0.001 | −0.46 (0.24) | 0.06 | 0.18 | −0.30 (0.23) | 0.20 | 0.39 | 0.16 (0.22) | 0.45 | 0.61 |
NADH-dep. ATP prod. * | 102 | −0.021 (0.006) | 0.001 | 0.008 | −0.47 (0.23) | 0.045 | 0.16 | −0.25 (0.22) | 0.26 | 0.46 | 0.22 (0.21) | 0.30 | 0.47 |
FADH2-dep. ATP prod. * | 103 | −0.027 (0.006) | <0.001 | 0.001 | −0.57 (0.24) | 0.020 | 0.10 | −0.55 (0.23) | 0.020 | 0.10 | 0.03 (0.22) | 0.91 | 0.94 |
GP * | 97 | −0.032 (0.007) | <0.001 | <0.001 | −0.62 (0.28) | 0.029 | 0.12 | 0.012 (0.27) | 0.97 | 0.97 | 0.64 (0.26) | 0.016 | 0.10 |
CCO * | 102 | −0.035 (0.008) | <0.001 | <0.001 | −0.22 (0.21) | 0.31 | 0.47 | −0.44 (0.22) | 0.051 | 0.17 | −0.22 (0.21) | 0.20 | 0.39 |
Basal * | 95 | −0.031 (0.008) | <0.001 | <0.001 | −0.52 (0.30) | 0.08 | 0.23 | −0.17 (0.29) | 0.55 | 0.68 | 0.35 (0.27) | 0.19 | 0.39 |
RCRu * | 95 | −0.003 (0.005) | 0.51 | 0.65 | −0.27 (0.18) | 0.14 | 0.35 | −0.38 (0.18) | 0.03 | 0.13 | −0.11 (0.16) | 0.49 | 0.64 |
SRC * | 95 | 0 (0.004) | 0.92 | 0.94 | 0.03 (0.16) | 0.85 | 0.93 | −0.14 (0.15) | 0.35 | 0.51 | −0.17 (0.14) | 0.22 | 0.41 |
PL/ROS * | 95 | 0.001 (0.005) | 0.88 | 0.94 | 0.27 (0.20) | 0.19 | 0.39 | 0.31 (0.20) | 0.12 | 0.33 | 0.04 (0.18) | 0.83 | 0.93 |
IRC | 95 | 0.001 (0.003) | 0.69 | 0.79 | −0.09 (0.10) | 0.35 | 0.51 | −0.13 (0.10) | 0.16 | 0.38 | −0.04 (0.09) | 0.64 | 0.75 |
RCR | 95 | −0.006 (0.007) | 0.38 | 0.53 | −0.30 (0.29) | 0.30 | 0.47 | −0.43 (0.28) | 0.13 | 0.33 | −0.13 (0.26) | 0.62 | 0.75 |
Mitochondrial Outcomes | N | Semi-Partial r | P | FDR | N | Semi-Partial r | P | FDR |
---|---|---|---|---|---|---|---|---|
With log white matter hyperintensity volume | With whole brain volume | |||||||
Citrate synthase activity * | 87 | −0.227 | 0.036 | 0.13 | 87 | 0.249 | 0.021 | 0.08 |
NADH-linked ATP production * | 86 | −0.172 | 0.115 | 0.25 | 86 | 0.158 | 0.149 | 0.33 |
FADH2-linked ATP production * | 87 | −0.264 | 0.014 | 0.08 | 87 | 0.246 | 0.023 | 0.08 |
Glycerophosphate-linked ATP production * | 79 | −0.091 | 0.427 | 0.67 | 79 | 0.064 | 0.576 | 0.63 |
Cytochrome oxidase activity * | 86 | −0.176 | 0.107 | 0.25 | 86 | 0.323 | 0.003 | 0.03 |
Glucose-Gln-fueled ATP production * | 81 | −0.330 | 0.003 | 0.03 | 81 | 0.213 | 0.058 | 0.16 |
RCRu * | 81 | −0.023 | 0.842 | 0.84 | 81 | 0.098 | 0.385 | 0.61 |
SRC * | 81 | −0.105 | 0.354 | 0.65 | 81 | 0.020 | 0.862 | 0.86 |
PL/ROS * | 81 | −0.040 | 0.727 | 0.84 | 81 | −0.070 | 0.540 | 0.63 |
IRC | 81 | 0.026 | 0.819 | 0.84 | 81 | 0.082 | 0.470 | 0.63 |
RCR | 81 | −0.060 | 0.599 | 0.82 | 81 | 0.135 | 0.231 | 0.42 |
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Wang, J.Y.; Napoli, E.; Kim, K.; McLennan, Y.A.; Hagerman, R.J.; Giulivi, C. Brain Atrophy and White Matter Damage Linked to Peripheral Bioenergetic Deficits in the Neurodegenerative Disease FXTAS. Int. J. Mol. Sci. 2021, 22, 9171. https://doi.org/10.3390/ijms22179171
Wang JY, Napoli E, Kim K, McLennan YA, Hagerman RJ, Giulivi C. Brain Atrophy and White Matter Damage Linked to Peripheral Bioenergetic Deficits in the Neurodegenerative Disease FXTAS. International Journal of Molecular Sciences. 2021; 22(17):9171. https://doi.org/10.3390/ijms22179171
Chicago/Turabian StyleWang, Jun Yi, Eleonora Napoli, Kyoungmi Kim, Yingratana A. McLennan, Randi J. Hagerman, and Cecilia Giulivi. 2021. "Brain Atrophy and White Matter Damage Linked to Peripheral Bioenergetic Deficits in the Neurodegenerative Disease FXTAS" International Journal of Molecular Sciences 22, no. 17: 9171. https://doi.org/10.3390/ijms22179171