Heterogeneous age-related breakdown of white matter structural integrity: implications for cortical “disconnection” in aging and Alzheimer’s disease

Abstract

Human and non-human primate data suggest that the structural integrity of myelin sheaths deteriorates during normal aging, especially in the late-myelinating association regions and may result in “disconnection” of widely distributed neural networks. Magnetic resonance imaging (MRI) was used to assess the heterogeneity of this process and its impact on brain aging and Alzheimer’s disease (AD) by evaluating early- and later-myelinating regions of the corpus callosum, the splenium (Scc) and genu (Gcc), respectively. Calculated transverse relaxation rates (R₂), an indirect measure of white matter structural integrity for the Gcc and Scc, were examined. The relationship between age and R₂ differed in the two regions. A quadratic (inverted U) function with an accelerating rate of decline beginning at age 31 best represented the Gcc pattern while the Scc decline was three-fold smaller, gradual, and linear. These data suggest that the severity of age-related myelin breakdown is regionally heterogeneous, consistent with the hypothesis that differences in myelin properties make later-myelinating regions more susceptible to this process. In AD this process is globally exacerbated, consistent with an extracellular deleterious process such as amyloid β-peptide toxicity. Non-invasive measures such as R₂ may be useful in primary prevention studies of AD.

Introduction

Magnetic resonance imaging (MRI) can be used to investigate the process of myelination in vivo [3], [66], [68]. Recent studies have confirmed post-mortem data showing that in the brain’s association regions, myelination continues until middle age [3], [23], [30], [59], [71] followed by a breakdown in the myelin sheaths, which is especially striking in late-myelinating fiber systems [4], [12], [28], [30].

Myelin-producing oligodendrocytes are heterogeneous depending on when in the process of brain development they differentiate to produce their myelin sheaths [52]. Later-differentiating oligodendrocytes ensheath many more axons with smaller axon diameters [35], [47] and may have different lipid properties [28]. This developmental heterogeneity may underlie the observed increased vulnerability of late-myelinating regions such as the frontal and temporal lobes [3], [71] to myelin breakdown [4], [30] that may promote the degenerative process resulting in AD (reviewed in [2]).

Changes in the structural integrity of myelin can be measured in vivo with MRI and have been demonstrated in normal aging and AD [4], [6], [7], [8]. In addition to increasing white matter volume, myelination reduces white matter water content [21], [49] and conversely, myelin breakdown increases it [19], [61]. Focal areas of myelin breakdown are easily identified visually on T₂-weighted MRI images as T₂ hyperintensities [29], [61]. Transverse relaxation time (T₂) measures are sensitive to differences in tissue water and can change by more than an order of magnitude depending on the proportion of “free” water (water whose motion is not restricted by close interactions with other molecules such as proteins and lipids) present in tissue [44], [48]; therefore, relatively small changes in MR detectable free water markedly alter T₂ [19], [29], [61], [66] (i.e. T₂ of water [such as cerebrospinal fluid] is well over 2000 ms, while T₂ of brain parenchyma is under 100 ms [44]). Analysis of relaxation time measurement is facilitated by the convention of transforming T₂ (measured in milliseconds) into transverse relaxation rates (R₂) (expressed in second⁻¹) using the formula (R₂=1/T₂×1000 ms/s). Calculated R₂ measurements can reveal brain myelination differences not visually discernible on T₂-“weighted” images and are a more sensitive indicator of myelination [21]. Myelination increases R₂ while myelin breakdown decreases it [4], [6], [19], [21], [27], [37], [40], [41], [45], [61].

Age-related myelin breakdown has been visualized on electron microscopy and consists primarily of splits in the lamellae of the myelin sheaths or ballooned sheaths in the absence of changes in or loss of neurons or synapses [42], [50]. In Alzheimer’s disease (AD), similar myelin abnormalities have been described in the absence of axonal damage [63], [67]. This pattern of myelin breakdown creates microscopic fluid filled spaces, increases free water, and thus decreases R₂ [17], [29]. Age-related myelin breakdown is also evident in the reduction of myelin staining in human and non-human primates [30], [32], [51] and increased white matter free water in imaging studies of aging and AD [4], [6], [7], [8], [9], [10], [17], [18], [24], [25], [43].

An accelerating trajectory of myelin breakdown with age that is similar to the accelerating age-related risk of developing AD has been observed in the frontal lobe region of healthy older individuals [4], [12], [30], [39]. We hypothesized that the severity of age-related myelin breakdown will be regionally heterogeneous depending on when in development myelination occurred [2], [4]. To test this hypothesis we chose the corpus callosum because it contains similarly oriented compact intrahemispheric fibers that are relatively homogeneous within limited subregions of the structure [47] and are devoid of crossing fibers tracts. We examined the later-myelinating genu of the corpus callosum (Gcc) that connects prefrontal association cortices and the early-myelinating splenium of the corpus callosum (Scc), which contains primarily sensory (visual) axons [35], [47]. We further hypothesized that additional insults associated with AD will exacerbate myelin breakdown in both regions, supporting the notion that the development of AD involves global extracellular deleterious factors, such as increased levels of amyloid β-peptide (Aβ) fibrils [26], that are superimposed on the ongoing aging process [2], [4].