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Cerebral blood flow is associated with cerebral microstructural integrity in normative aging1National Institute on Aging, Baltimore, MD, United States
Synopsis
Maintenance of cerebral tissue homeostasis is particularly sensitive to deficits in cerebral blood flow (CBF) and concomitant hypoxia and hypoglycemia. However, little work has been conducted to investigate the potential association between deficits in CBF and deterioration of brain microstructure, especially in normative aging. The results of our analysis, conducted on a large cohort of cognitively unimpaired adults, of the association between CBF and several MRI metrics of cerebral microstructural integrity, indicate that low CBF values correspond to low tissue integrity. These results provide further evidence of the intimate relationship between neurovascular physiology and brain integrity throughout normative aging.
INTRODUCTION
Gray matter (GM) and white matter (WM) tissue deterioration and decline in cerebral blood flow (CBF) are central features of several neurodegenerative diseases (1-6). Brain tissue maintenance is an energy-demanding process, making it particularly sensitive to hypoperfusion and concomitant hypoxia and hypoglycemia. Despite its central importance, little is known about the association between blood flow and brain microstructural integrity, including in normative aging (7-9). Examining the extent of this potential relationship is sine qua non for understanding the interactions between CBF and tissue integrity in impaired populations. Here, we investigated the regional association between CBF and deterioration of cerebral microstructural integrity probed using various MR imaging metrics in a large cohort of well-characterized adults.METHODS
Study cohort and data acquisitionThe study cohort consisted of 94 subjects (age 50.7±19.2years, 38 women) spanning the age range between 22 and 88 years. Participants underwent i) a pseudo-continuous arterial spin labeling (pCASL) imaging for CBF mapping (11,12). This consisted of acquiring control, labeled, and proton density (PD) images at labeling duration of 1.8 s, post-labeling duration of 2 s, and 30 signal averages; details of this imaging protocol can be found in (10), ii) our BMC-mcDESPOT imaging for myelin water fraction (MWF) mapping (11-14), a surrogate of myelin content, and longitudinal and transverse relaxation rates (R1 and R2) mapping, sensitive metrics to myelin content, axonal density, dendritic density, synaptic density, and iron content (15); details of this and the mcDESPOT imaging protocol can be found in (11), and iii) diffusion tensor imaging (DTI) for fractional anisotropy (FA), and mean, radial and axial diffusivities (FA, MD, RD and AxD) mapping; details about this imaging protocol can be found in (16, 17).
Image processing
For each subject, whole-brain MWF, R1 and R2 maps were generated using the BMC-mcDESPOT (12-14), DESPOT1 and DESPOT2 analyses (18), whole-brain maps of FA, MD, RD and AxD maps were derived from the DTI dataset using FSL (16, 17, 19), and a whole-brain CBF map was generated from the pCASL dataset using the NESMA-ASL analysis to improve accuracy and precision in CBF determination (10, 20). All derived parameter maps were nonlinearly registered to the MNI atlas using FSL (19). Finally, mean parameter values were calculated in six WM and GM regions-of-interest (ROIs) defined from MNI.
Statistical analysis
For each ROI, the effect of CBF on each MR parameter, that is, MWF, R1, R2, FA, MD, RD, or AxD, was investigated using multiple linear regression with the mean MR parameter value within the ROI as the dependent variable and CBF, age, and age2 as the independent variables.
RESULTS & DISCUSSION
Figure 1 show plots of the relationship between CBF and each MR parameter studied for representative ROIs. It is readily seen that lower CBF values correspond to lower FA, R1, R2 and MWF values or higher MD, AxD and RD values. Our statistical analysis indicates that these associations between CBF and these MR parameters of tissue integrity were statistically significant (pCBF<0.05) or close to significance (pCBF<0.1) in several GM and WM structures examined (Table 1). Interestingly, this association was more pronounced between CBF and MWF as well as CBF and AxD; this agrees with literature and our recent work in this much larger cohort size (7-9), suggesting that myelin sheets, axons, dendrites, and synapses are vulnerable to deficits in blood supply. Indeed, this functional relationship has been documented in animal studies showing that glial cells, including oligodendrocytes, the cells responsible for myelin synthesis and trophic support to neurons, are vulnerable to blood flow deficits, and that loss of these cells may occur rapidly in response to chronic hypoperfusion (21, 22). Further, deterioration of GM tissue due to deficits in CBF would be expected as several studies have shown that high consumption of energy is crucial for normal functioning of the brain. It has been shown that a substantial amount of this energy is used to support synaptic activity (23), while dendritic structures were rapidly distorted after acute or chronic ischemia (24). Therefore, inadequate supply of blood glucose and oxygen to the cortical tissue may lead to neuronal and glia death. Therefore, our results provide further evidence of this association in normative aging.Finally, the effect of age on all MR parameters studied was statistically significant in all ROIs evaluated, as expected. Similarly, in agreement with literature (11, 25-28), the quadratic effect of age, age2, was significant in most brain regions for all observed metrics (Table 1). This quadratic pattern reflects brain maturation until middle age followed by a rapid phase of degeneration at older ages.
CONCLUSIONS
These findings suggest that blood flow may significantly impact GM and WM integrity. We expect that this work may lay the foundation for investigations to further establish this link and to clarify the nature of early brain damage in MRI markers of neurodegeneration, including small vessel ischemic disease or Alzheimer’s disease. These studies may lead to new neuroimaging biomarkers of brain microstructure and function for disease progression.Acknowledgements
This work was supported by the Intramural Research Program of the National Institute on Aging of the National Institutes of Health.References
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