Characterizing the normative profile of ¹⁸F-FDG PET brain imaging: Sex difference, aging effect, and cognitive reserve

Abstract

The aim of this study was to investigate findings of positron emission tomography with ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG PET) in normal subjects to clarify the effects of sex differences, aging, and cognitive reserve on cerebral glucose metabolism. Participants comprised 123 normal adults who underwent ¹⁸F-FDG PET and a neuropsychological battery. We used statistical parametric mapping (SPM8) to investigate sex differences, and aging effects. The effects of cognitive reserve on ¹⁸F-FDG uptake were investigated using years of education as a proxy. Finally, we studied the effect of cognitive reserve on the recruitment of glucose metabolism in a memory task by dichotomizing the data according to educational level. Our results showed that the overall cerebral glucose metabolism in females was higher than that in males, whereas male participants had higher glucose metabolism in the bilateral inferior temporal gyri and cerebellum than females. Age-related hypometabolism was found in anterior regions, including the anterior cingulate gyrus. These areas are part of the attentional system, which may decline with aging even in healthy elderly individuals. Highly educated subjects revealed focal hypermetabolism in the right hemisphere and lower recruitment of glucose metabolism in memory tasks. This phenomenon is likely a candidate for a neural substrate of cognitive reserve.

Introduction

With today's increasing life expectancy, precise diagnosis of neurodegenerative disorders has become important. Imaging of cerebral glucose metabolism with ¹⁸F-fluorodeoxyglucose positron emission tomography (¹⁸F-FDG PET) has been increasingly applied to aid in the clinical diagnosis of Alzheimer's disease (AD), frontotemporal lobar degeneration (FTLD), and dementia with Lewy bodies (DLB) (Bohnen et al., 2012). Voxel-based statistical image analyses such as three-dimensional stereotactic surface projection (3D-SSP) (Minoshima et al., 1995) and statistical parametric mapping (SPM) (Friston, 1997) have been reported to improve diagnostic accuracy compared with conventional images. In these analyses, a precise understanding of the profile of a normative reference image (normative database) is essential for an accurate diagnosis. However, there remains debate with respect to the effects of sex, aging, and educational attainment on cerebral glucose metabolism.

First, findings of sex effects on normal cerebral glucose metabolism have been inconsistent (Andreason et al., 1994, Loessner et al., 1995, Kawachi et al., 2002, Willis et al., 2002, Fujimoto et al., 2008, Iseki et al., 2010, Chen et al., 2011). Accurate characterization of sex differences in normal cerebral glucose metabolism would aid in arriving at a precise diagnosis, in predicting disease progression, and elucidating underlying disease mechanisms. Second, despite the general consensus that reduction in brain metabolism with age tends to occur in the anterior part of the brain (Kuhl et al., 1982, Ivançević et al., 2000, Newberg and Alavi, 2010), it is unclear whether there are sex differences in the effects of aging on brain glucose metabolism. The trajectory of the neuropsychological profile with aging varies according to sex (Bleecker et al., 1988, Tisserand and Jolles, 2003); thus, sex-specific aging effects on brain metabolism may also exist. Finally, the effects of educational level on ¹⁸F-FDG uptake during the resting state and in tasks investigating memory function have not yet been fully investigated. Education, occupational experience, and leisure activities are thought to improve “cognitive reserve”, which may render individuals relatively resistant to brain damage before functional deficits emerge (Stern, 2009). Although the mechanistic underpinnings of cognitive reserve remain to be elucidated, past reports have indicated that educational level plays a pivotal role in cognitive reserve. Investigating educational effects on brain activity would contribute to further understanding of cognitive reserve.

In the present study, we used a voxel-based analytic approach implemented in SPM to study the effects of sex, age, and education on brain glucose metabolism measured with ¹⁸F-FDG PET. Furthermore, the brain regions positively correlated to memory function were analyzed separately by subgroups divided according to their educational levels. Through this analysis, we investigated whether educational attainment is a moderating factor in brain–behavior correlations.