Age changes in myelinated nerve fibers of the cingulate bundle and corpus callosum in the rhesus monkey

Abstract

Aging is accompanied by deficits in cognitive function, which may be related to the vulnerability of myelinated nerve fibers to the normal process of aging. Loss of nerve fibers, together with agerelated alterations in myelin sheath structure, may result in the inefficient and poorly coordinated conduction of neuronal signals. Until now, the ultrastructural analysis of cerebral white matter fiber tracts associated with frontal lobe areas critical in cognitive processing has been limited. In this study we have analyzed the morphology and area number density of myelinated nerve fibers in the cingulate bundle and genu of the corpus callosum in behaviorally assessed young, middle aged, and old rhesus monkeys (Macaca mulatta). In both structures, normal aging results in a 20% decrease in the number of myelinated nerve fibers per unit area, while remaining nerve fibers exhibit an increasing frequency of degenerative changes in their myelin sheaths throughout middle and old age. Concomitantly, myelination continues in older monkeys, suggesting ongoing, albeit inadequate, reparative processes. Despite similar patterns of degeneration in both fiber tracts, only the age-related changes in the cingulate bundle correlate with declining cognitive function, underscoring its role as a critical corticocortical pathway linking the medial prefrontal, cingulate, and parahippocampal cortices in processes of working memory, recognition memory, and other higher cognitive faculties. These results further demonstrate the important role myelinated nerve fiber degeneration plays in the pathogenesis of age-related cognitive decline.

Age-related changes in human and non-human primate white matter: from myelination disturbances to cognitive decline

“…Using template-driven segmentation to analyze this cohort also revealed a significant loss of WM with stability of GM (Wisco et al 2008). The loss of WM volume likely reflects the age-related axon degeneration detected by Bowley et al (2010), but would not reflect the ubiquitous myelin pathology. To address this, DTI scans were acquired on a different cohort of aged monkeys.…”

“…Recently, both the fluid filled and dense inclusions were quantified in the genu of the corpus callosum and in the cingulum bundle (Bowley et al 2010). Analyzing randomly selected fields in the electron microscope, it was shown that both forms of pathology increase steadily with age beginning in middle-aged monkeys by 15 years of age (equivalent to a 45-year-old human) where about 2% of fibers shows one or the other form of pathology.…”

Candidate molecular pathways of white matter vulnerability in the brain of normal aging rhesus monkeys

“…There is an increase of activated astrocytes and microglia in the white matter (Sloane et al 1999;Sloane et al 2000;Shobin et al 2017). Axons are also lost in the white matter and can be seen in the electron microscope as degenerating axons contained within degenerating myelin sheaths in keeping with the observed decrease in density of myelinated axons (Bowley et al 2010;Peters et al 2010). These alterations in white matter also correlated with age-related cognitive decline.…”

“…If transport of the protein to or from the synapse in the axons and dendrites with age was altered, signaling resulting from the activity-dependent regulated release of the protein would be decreased even more. Such a decrease in signaling could then underlie the observed reductions in spines and atrophy of dendrites (for review see (Dickstein et al 2013)) as well as the loss of long axons (Bowley et al 2010;Peters et al 2010) observed in the normal aging monkey brain. There are conflicting reports as to whether proBDNF is also released from the neuron in an activity dependent manner to exert a biological effect through the binding to the p75 NGFR receptor or if it is simply an intermediary protein in the formation of mBDNF with little significance for signaling (Matsumoto et al 2008;Yang et al 2009).…”

“…Moreover, both electron microscopic (Bowley et al 2010) and biochemical studies (Duce et al 2008;Hinman et al 2008) have shown that the white matter changes are associated with a variety of pathological changes in myelin. Some of these changes in white matter include a decrease with age of the messenger ribonucleic acid (mRNA) and protein levels of klotho, a longevity factor important for myelin homeostasis (Duce et al 2008;Chen et al 2013).…”