Quantitative age-dependent differences in human brainstem myelination assessed using high-resolution magnetic resonance mapping

Abstract

Previous in-vivo magnetic resonance imaging (MRI)-based studies of age-related differences in the human brainstem have focused on volumetric morphometry. These investigations have provided pivotal insights into regional brainstem atrophy but have not addressed microstructural age differences. However, growing evidence indicates the sensitivity of quantitative MRI to microstructural tissue changes in the brain. These studies have largely focused on the cerebrum, with very few MR investigations addressing age-dependent differences in the brainstem, in spite of its central role in the regulation of vital functions. Several studies indicate early brainstem alterations in a myriad of neurodegenerative diseases and dementias. The paucity of MR-focused investigations is likely due in part to the challenges imposed by the small structural scale of the brainstem itself as well as of substructures within, requiring accurate high spatial resolution imaging studies. In this work, we applied our recently developed approach to high-resolution myelin water fraction (MWF) mapping, a proxy for myelin content, to investigate myelin differences with normal aging within the brainstem. In this cross-sectional investigation, we studied a large cohort (n = 125) of cognitively unimpaired participants spanning a wide age range (21-94 years) and found a decrease in myelination with age in most brainstem regions studied, with several regions exhibiting a quadratic association between myelin and age. We believe that this study is the first investigation of MWF differences with normative aging in the adult brainstem. Further, our results provide reference MWF values.

Keywords: BMC-mcDESPOT; Brainstem; MRI; Myelin water fraction; Normal aging.

Figure 1.. Number of participants per age-decade and sex within the study cohort.

Figure 2:. Visualization of the white matter and deep gray matter ROIs in the brainstem.

1) Subthalamic nucleus, 2) Cerebral peduncle, 3) Substantia nigra, 4) Red nucleus, 5) Middle cerebellar peduncle, 6) Corticospinal tract, 7) Pontine tract, 8) Lemniscus tract, 9) Superior cerebellar peduncle, 10) Inferior cerebellar peduncle, 11) Midbrain, 12) Pons, and 13) Medulla. The brain images were obtained from the standard MNI atlas provided in FSL.

Figure 3:. Myelin water fraction (MWF) represented as averaged participant maps calculated over 10-year intervals.

Results are shown for four representative slices covering the main brainstem structures. Slices 1 and 2 are representative axial views of the midbrain while slices 3 and 4 are representative axial views of the pons and medulla, respectively. The red bars on the anatomical images indicate the location of the slices. Visual inspection of MWF maps shows an increase in MWF values from early adulthood through middle age, that is, from 20-29 years through 40-49 years, followed by a more rapid decrease, in several brainstem substructures.

Figure 4:. Plots of myelin water fraction (MWF) ROI values as a function of age (N = 125) for white and deep grey matter substructures within the brainstem.

For each region, the coefficient of determination, R², and the significance of the linear regression model, p, are reported. All regions investigated showed linearly decreasing trends of MWF with age while exhibiting variation in slope.

Figure 5:. Plots of myelin water fraction (MWF) ROI values as a function of age (N = 125) for six of the substructures also highlighted in Fig. 4, but for which quadratic trends of MWF were significant.

For each region, the coefficient of determination, R², and the significance of the overall regression model, p, are reported. These selected regions clearly exhibited a quadratic trend of age on MWF, with significant or close to significant p values. This suggests progressive myelination continuing into middle age followed by more rapid myelin loss. We note that similar trends have recently been reported in the cerebrum (7, 21).