Abstract
Tremendous progress has been made over the last few years in understanding how sleep and amyloid-β (Aβ) cooperate to speed up the progression of Alzheimer’s disease (AD). However, it remains unknown whether sleep deficits also interact with other risk factors that exacerbate the pathological cascade of AD. Based on evidence showing that higher levels of homocysteine (HCY) and sleep loss increase oxidative damage, we here investigate whether the relationship between HCY and total antioxidant capacity (TAC) is mediated by changes in objective sleep in healthy older (HO, N = 21) and mild cognitive impairment (MCI, N = 21) subjects. Results revealed that reduced TAC levels in MCI was significantly correlated with increased HCY, shorter sleep duration, lower sleep efficiency, and reduced volume of temporal regions. However, only the HCY-TAC association showed diagnostic value, and this relationship was mediated by poorer sleep quality in MCI patients. We further showed that HCY-related cerebral volume loss in MCI depended on the serial relationship between poorer sleep quality and lower TAC levels. These findings provide novel insights into how impaired sleep may contribute to maintain the relationship between HCY and oxidative stress in prodromal AD, and offer empirical foundations to design therapeutic interventions aimed to weaken this link.
Highlights
One of the hallmarks of aging is a pervasive accumulation of mitochondrial reactive oxygen species (ROS) followed by the decreased ability of cells to defend against and recover from oxidative insults[1]
Factor for a variety of neurodegenerative conditions16; 2) the relationship between HCY-sleep will be present in both healthy older (HO) and mild cognitive impairment (MCI), as inferred from studies showing that elevated HCY levels are more frequent in subjects with a short sleep duration regardless of their clinical status17; 3) MCI patients will show a stronger relationship between sleep-total antioxidant capacity (TAC) than HO subjects, as supported by evidence showing associations between shorter sleep durations and decreased TAC levels in different clinical populations compared with normal subjects[18, 19]; and 4) all these factors (i.e., HCY, TAC and sleep) will be related to each other in MCI because of their well-recognized effects on Aβ accumulation, which would account for HCY-sleep associated patterns of brain atrophy[11]
The present study provides the first evidence that poorer sleep quality in MCI patients, in addition to being significantly associated with reduced TAC and increased HCY levels, mediated the relationship between HCY and TAC, two factors actively involved in the pathological cascade of AD4, 10
Summary
One of the hallmarks of aging is a pervasive accumulation of mitochondrial reactive oxygen species (ROS) followed by the decreased ability of cells to defend against and recover from oxidative insults[1]. Sleep loss has been associated with ROS-induced oxidative stress in middle-aged flies[12], activation of a maladaptive ER stress response in old mice[13], and Aβ aggregation in transgenic mouse models of amyloidosis[14]. It remains unknown whether the association between HCY levels and brain atrophy is influenced by the relationship between total antioxidant capacity and sleep quality. Factor for a variety of neurodegenerative conditions16; 2) the relationship between HCY-sleep will be present in both HO and MCI, as inferred from studies showing that elevated HCY levels are more frequent in subjects with a short sleep duration regardless of their clinical status17; 3) MCI patients will show a stronger relationship between sleep-TAC than HO subjects, as supported by evidence showing associations between shorter sleep durations and decreased TAC levels in different clinical populations compared with normal subjects[18, 19]; and 4) all these factors (i.e., HCY, TAC and sleep) will be related to each other in MCI because of their well-recognized effects on Aβ accumulation, which would account for HCY-sleep associated patterns of brain atrophy[11]
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