Sleep Fragmentation, Cerebral Arteriolosclerosis, and Brain Infarct Pathology in Community-Dwelling Older People
Background and Purpose—Although several forms of sleep disruption are associated with stroke, few studies have examined the relationship between sleep and histopathologic measures of cerebrovascular disease. We tested the hypothesis that greater sleep fragmentation is associated with a higher burden of cerebral vessel and infarct pathology at autopsy.
Methods—We used ordinal logistic regression models to relate sleep fragmentation measured by actigraphy to the severity of arteriolosclerosis, atherosclerosis, and cerebral amyloid angiopathy, and the number of macroscopic and microscopic infarcts assessed by structured brain autopsy in 315 participants from the Rush Memory and Aging Project.
Results—Greater sleep fragmentation was associated with more severe arteriolosclerosis (odds ratio, 1.27; 95% confidence interval, 1.02–1.59; P=0.03 per 1 SD greater sleep fragmentation) and more subcortical macroscopic infarcts (odds ratio, 1.31; 95% confidence interval, 1.01–1.68; P=0.04). These associations were independent of established cardiovascular risk factors and diseases, and several medical comorbidities.
Conclusions—Sleep fragmentation is associated with arteriolosclerosis and subcortical infarcts in older adults.
Sleep abnormalities are associated with imaging markers of cerebrovascular pathology and with clinical stroke.1,2 However, some cerebrovascular pathologies, such as arteriolosclerosis, cerebral amyloid angiopathy, and microscopic infarcts, can only be quantified by histopathology and with few exceptions,3 their associations with sleep are unknown. This is important because these pathologies contribute not only to clinical stroke but also to chronic progressive cognitive4 and motor5 impairment.
We tested the hypothesis that greater sleep fragmentation is associated with more severe arteriolosclerosis, atherosclerosis, and cerebral amyloid angiopathy and more macroscopic and microscopic pathological infarcts in older adults.
Full details are available in the online-only Data Supplement.
We studied 315 autopsied individuals with ≥1 actigraphic recording from the Rush Memory and Aging Project, a community-based cohort study of aging with brain donation on death.
Sleep fragmentation was assessed biennially by 10 days of ambulatory actigraphy using the metric kRA.6 As described in the online-only Data Supplement, kRA correlates strongly with polysomnographic measures of fragmentation, including the arousal index (R=+0.6, P<0.0001) and sleep efficiency (R=−0.6, P<0.0001). The mean kRA was 0.029 which at steady-state would correspond to 6.96 movement arousals per hour.
As in previous work with other risk factors,7 where an individual had >1 actigraphic measurement before autopsy, we took the average of all measurements. This best reflects the cumulative impact of sleep fragmentation, minimizing the effects of individual measurements, which could reflect acute or terminal illness. The average participant had 3 recordings.
We used an ordinal outcome of 0, 1, or ≥2 infarcts to summarize the number of cortical and subcortical microscopic and macroscopic infarcts quantified histopathologically as previously described.8 The severity of atherosclerosis, arteriolosclerosis, and amyloid angiopathy were quantified by gross and histopathologic examination of the Circle of Willis and specific brain regions, and summarized using 4-point semiquantitative scales as previously described.8,9
Additional actigraphic and clinical covariates were quantified as described in the online-only Data Supplement. We used ordinal logistic regression models to relate sleep fragmentation to the severity of each vessel pathology, or the number of subcortical or cortical infarcts, adjusting for potential confounders as described in the online-only Data Supplement.
The mean age at death of the 315 participants was 90.4 years; 70% were female (Table I in the online-only Data Supplement); 29% had a clinical stroke; and 61% of participants had ≥1 moderate to severe vascular pathology.
Each 1 SD higher sleep fragmentation was associated with nearly 30% higher odds of more severe arteriolosclerosis (Table 1). By contrast, sleep fragmentation was not associated with the severity of atherosclerosis or amyloid angiopathy.
Each 1 SD higher sleep fragmentation was also associated with >30% higher odds of having more subcortical macroscopic infarcts (Table 2); by contrast sleep fragmentation was not associated with cortical macroscopic infarcts (column 2), with microscopic infarcts (columns 3–4), or with clinically evident strokes (odds ratio, 0.95; 95% confidence interval, 0.72–1.22; P=0.69). Associations were similar for lacunar (≥1 mm; odds ratio, 1.30; 95% confidence interval, 1.00–1.68) and nonlacunar (<1 mm; odds ratio, 1.36; 95% confidence interval, 0.96–1.88) infarcts.
Adjusting for arteriolosclerosis attenuated the association between sleep fragmentation and subcortical infarcts by <5%, indicating that arteriolosclerosis does not account for this association (Table II in the online-only Data Supplement).
The associations between sleep fragmentation and arteriolosclerosis (Table III in the online-only Data Supplement) and subcortical infarcts (Table IV in the online-only Data Supplement) remained significant after adjusting for potential confounders, including date of actigraphy and time of autopsy, total daily rest and activity; cardiovascular risk factors and diseases, and several medical comorbidities including Alzheimer pathology, pain, depression, and heart failure. In models adjusted for pulmonary and renal function, the associations between sleep fragmentation and arteriolosclerosis were minimally attenuated. Similarly, in models adjusted for circadian irregularity, dementia, coronary disease, and renal function, the associations with subcortical infarcts were minimally attenuated. Dementia did not modify the associations with arteriolosclerosis (P=0.29) or subcortical infarcts (P=0.86).
Our findings may be interpreted in 3 ways: (1) one possibility is that cerebrovascular pathology causes sleep fragmentation. We previously showed that cell loss in the intermediate nucleus is associated with sleep fragmentation.10 However, the hypothalamus and other sleep centers represent a tiny volume of the brain and hypothalamic infarction is unusual because of its rich blood supply.11 Moreover, although individuals with clinical stroke symptoms should be the most likely to have stroke-induced sleep fragmentation, the associations were independent of clinically evident stroke. (2) Although the associations between sleep fragmentation and cerebrovascular pathology were independent of established risk factors, an unmeasured latent variable may have predisposed to both. (3) Sleep fragmentation may contribute to cerebrovascular pathology. In support of this, other forms of sleep disruption are associated with physiological risk factors for cerebrovascular pathology including diurnal and nocturnal hypertension12,13 and abnormal glucose processing,12 among others, which may be mechanisms linking sleep fragmentation to cerebrovascular pathology.
This study had limitations. First, it was observational, limiting determination of causality. Second, although we showed that kRA correlates strongly with polysomnographic measures, and unlike polysomnography is well tolerated, does not perturb sleep, and can record over days, it does not directly measure brain electric activity. Third, actigraphy does not distinguish between causes of sleep fragmentation. We adjusted for several of these in our analyses, including clinical stroke, heart disease, dementia, depression, pain, and pulmonary and renal function. However, sleep apnea, that is common in patients with stroke,14 was not specifically measured, nor were periodic limb movements in sleep. This is relevant given our finding that in patients with sleep apnea, kRA may be a marker of sleep apnea severity (online-only Data Supplement). Fourth, although key covariates were objectively quantified, including physical activity, body mass index, blood pressure, pulmonary function, and renal function, others were self-reported, including heart disease, smoking, and diabetes mellitus.
Notwithstanding these limitations, these data show that greater sleep fragmentation is associated with more arteriolosclerosis and macroscopic subcortical infarct pathology. Further work is needed to clarify whether these are consequences or causes of sleep fragmentation, the role of specific contributors to sleep fragmentation (eg, sleep apnea), and underlying biological mechanisms.
Sources of Funding
National Institutes of Health R01AG043379 R01AG15819 R01AG17917, and R01NS078009, Heart and Stroke Foundation of Ontario 7437, and Canadian Institutes of Health Research MOP125934, MMC112692, and MSH136642.
The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.115.011608/-/DC1.
- Received September 23, 2015.
- Revision received November 9, 2015.
- Accepted November 10, 2015.
- © 2016 American Heart Association, Inc.
- Gorelick PB,
- Scuteri A,
- Black SE,
- Decarli C,
- Greenberg SM,
- Iadecola C,
- et al
- Zheng JJ,
- Delbaere K,
- Close JC,
- Sachdev PS,
- Lord SR.
- Buchman AS,
- Leurgans SE,
- Nag S,
- Bennett DA,
- Schneider JA.
- Lim AS,
- Ellison BA,
- Wang JL,
- Yu L,
- Schneider JA,
- Buchman AS,
- et al
- Scheer FA,
- Hilton MF,
- Mantzoros CS,
- Shea SA.
- Ross AJ,
- Yang H,
- Larson RA,
- Carter JR.