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Taken together, these data suggest that noradrenergic LC projection system integrity may have a large role in mediating the changes from normal cognition (NC) to cognitive deterioration during AD. Recent MRI advancements in in vivo LC imaging have underscored this concept by noting that: 1) higher educational attainment and verbal intelligence correlate with stronger LC signal ( 12), 2) older adults displaying LC volumetric integrity similar to younger adults perform better on learning and memory tasks ( 13), and 3) LC MRI findings may serve as a biomarker for AD progression ( 14–18). episodic memory, working memory, semantic memory, perceptual speed) ( 4), similar to data showing that higher LC neuronal density is associated with slower rates of antemortem cognitive decline ( 11).
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Previously, we demonstrated that the extent of LC neuron loss observed postmortem is associated with a worsening of antemortem performance in multiple cognitive domains (e.g. Locus coeruleus (LC) projection neurons, which transmit norepinephrine to mediate cognitive functions such as vigilance and attention, memory storage and retrieval, executive function, and affect ( 1–3) undergo extensive degeneration in the putative prodromal stage of Alzheimer disease (AD) termed mild cognitive impairment (MCI) ( 4–6), supporting the longstanding hypothesis that LC degeneration is a key feature of AD pathogenesis ( 4–10). Pontine perfusion, as well as LC neuronal metabolic and redox function, may impact noradrenergic LC modulation of cognition during the preclinical and prodromal stages of AD.Īlzheimer disease, Arteriolosclerosis, Locus coeruleus, Mild cognitive impairment, Oxidative stress, Pons, Resilience INTRODUCTION In contrast, increasing pontine arteriolosclerosis severity scores and LC oxidative stress burden significantly separated the NC-LP/HP and MCI/AD groups via comparative, correlation, and regression analysis. There was a trend for a step-wise ∼20% loss of LC neuron number between the NC-LP, NC-HP and MCI subjects despite a successive, significant ∼80%–100% increase in tau pathology between these groups. In addition, the severity of pontine arteriolosclerosis in each subject was compared across the groups. We approached this problem by quantifying the number of LC neurons and the percentage of LC neurons bearing AT8 tau pathology, TDP-43 pathology, or a marker for DNA/RNA oxidative damage, in well-characterized subjects diagnosed as normal cognition-low AD pathology (NC-LP), NC-high AD pathology (NC-HP), MCI, or mild/moderate AD. However, the extent to which LC degenerative processes differentiate cognitively normal, “resilient” subjects bearing a high AD pathological burden from those with MCI or AD remains unclear. Locus coeruleus (LC) neurodegeneration is associated with cognitive deterioration during the transition from normal cognition to mild cognitive impairment (MCI) and Alzheimer disease (AD).