Abstract
Normal aging is characterized by declines in processing speed, learning, memory, and executive function even in the absence of neurodegenerative diseases such as Alzheimer's Disease (AD). In normal aging monkeys and humans, neuronal loss does not account for cognitive impairment. Instead, loss of white matter volume and an accumulation of myelin sheath pathology begins in middle age and is associated with cognitive decline. It is unknown what causes this myelin pathology, but it likely involves increased neuroinflammation in white matter and failures in oligodendrocyte function (maturation and repair). In frontal white matter tracts vulnerable to myelin damage, microglia become chronically reactive and secrete harmful pro-inflammatory cytokines. Despite being in a phagocytic state, these microglia are ineffective at phagocytosing accruing myelin debris, which directly inhibits myelin sheath repair. Here, we asked whether reported age-related increases in pro-inflammatory markers were accompanied by an adaptive immune response involving T cells. We quantified T cells with immunohistochemistry in the brains of 34 cognitively characterized monkeys and found an age-related increase in perivascular T cells that surround CNS vasculature. We found a surprising age-related increase in T cells that infiltrate the white matter parenchyma. In the cingulum bundle the percentage of these parenchymal T cells increased with age relative to those in the perivascular space. In contrast, infiltrating T cells were rarely found in surrounding gray matter regions. We assessed whether T cell infiltration correlated with fibrinogen extravasation from the vasculature as a measure of BBB leakiness and found no correlation, suggesting that T cell infiltration is not a result of passive extravasation. Importantly, the density of T cells in the cingulum bundle correlated with microglial reactivity and with cognitive impairment. This is the first demonstration that T cell infiltration of white matter is associated with cognitive decline in the normal aging monkey.
Highlights
Even in the absence of pathologic neurodegeneration, impairments in learning, memory, executive function, and processing speed begin as early as the third decade [1] making cognitive decline a hallmark of both healthy and neurodegenerative brain aging
The observations reported here show that T cells infiltrate the aged brain white matter in the absence of infection, damage or blood brain barrier breakdown
This T cell infiltration into the aging white matter parenchyma constitutes a novel observation that may reflect the mechanism by which cells of the adaptive immune system, during normal aging, contribute to neuroinflammation, white matter pathology and ensuing cognitive impairments
Summary
Even in the absence of pathologic neurodegeneration, impairments in learning, memory, executive function, and processing speed begin as early as the third decade [1] making cognitive decline a hallmark of both healthy and neurodegenerative brain aging. Rhesus monkeys have a ratio of white to gray matter similar to humans and exhibit an age-related decrease in white matter volume and increase in myelin damage which correlate with cognitive decline [17,18,19]. Diffusion imaging in rhesus macaques confirms the same differential vulnerability of white matter tracts observed in humans, with frontal tracts exhibiting disruption while other white matter tracts such as the internal capsule remain stable with age; and these tract disturbances correlate with cognitive impairment [20]. Ultrastructural examination of our monkey brains has demonstrated that white matter pathology begins with splitting of the sheath and formation of balloons filled with degenerating cytoplasm or fluid [21, 22] Such defects are present in
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