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Sleep, Circadian Rhythms, and Mechanisms of Cognitive Decline in the Human Brain

Award Number: R01AG052488
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/15/2017
PERIOD OF PERFORMANCE END DATE: 02/28/2025

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Sleep, Circadian Rhythms, and Mechanisms of Cognitive Decline in the Human Brain - Sleep and circadian disruption, including sleep apnea, sleep fragmentation, and circadian rhythm irregularity, affect millions of Americans, and are associated with impaired cognition and Alzheimer’s disease (AD). Challenges in applying standard techniques (e.g. polysomnography) in ambulatory settings to quantify sleep and circadian disruption in large numbers of community-dwelling older adults, and in obtaining detailed cognitive assessments and brain tissue from the same individuals, have left knowledge gaps. Thus, although sleep and circadian rhythm disruption affect millions of older Americans, there are few data concerning the contribution of their different forms to the growing number of older adults with cognitive impairment and dementia, and associated brain mechanisms. This study aims to fill these gaps. The overall goal of this study is to quantify the contributions of, and identify brain mechanisms linking, sleep and circadian rhythm disruption to cognitive decline and incident AD in older adults. In compelling preliminary work, we developed and applied a new method of measuring sleep fragmentation in the community setting using actigraphy, the non-invasive continuous measurement of movement using a watch-like device. In older adults, we found that higher sleep fragmentation is associated with 1) a greater risk of incident AD, 2) more brain arteriolosclerosis and subcortical strokes at autopsy, and 3) a higher burden of AD pathology in APOE e4 carriers. However, sleep fragmentation is only one type of sleep disruption, and its impact cannot be understood without simultaneously examining the impact of common sleep disorders such as sleep apnea, which may affect up to half of older adults. To extend these findings, we propose to use a portable battery of 2 wearable devices measuring continuous peripheral arterial tonometry, oximetry, and actigraphy to simultaneously quantify 5 key forms of sleep and circadian disruption in 780 older adults in the Rush Memory and Aging Project (R01AG17911). These will include 1) sleep apnea, 2) sleep duration, 3) sleep architecture, 4) sleep fragmentation, and 5) circadian irregularity. These measurements will be combined with donated cognitive and other clinical data, as well as post-mortem histopathology and brain MRI indices from decedents, to elucidate the brain correlates of sleep and circadian disruption in community-dwelling adults, and their impact on cognitive impairment and incident AD dementia. By overcoming key translational barriers, this study will fill important gaps in our knowledge concerning the burden and brain correlates of 5 key forms of sleep and circadian disruption in old age. This offers the potential to leverage sleep and circadian interventions to decrease the growing burden of cognitive impairment and AD, and for targeted therapies to improve brain health for the millions of Americans who experience sleep or circadian rhythm dysfunction.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = -$334,000 )
2025	2021	SUNNYBROOK RESEARCH INSTITUTE	2075 BAYVIEW AVE	TORONTO	ON			CAN	Aging Research	000	5	6/30/2025	NON-COMPETING CONTINUATION	-$334,000
														Subtotal = -$334,000

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2021	SUNNYBROOK RESEARCH INSTITUTE	2075 BAYVIEW AVE	TORONTO	ON			CAN	Aging Research	000	5	6/29/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	SUNNYBROOK RESEARCH INSTITUTE	2075 BAYVIEW AVE	TORONTO	ON			CAN	Aging Research	000	5	3/6/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $687,355 )
2021	2021	SUNNYBROOK RESEARCH INSTITUTE	2075 BAYVIEW AVE	TORONTO	ON			CAN	Aging Research	000	5	3/17/2021	NON-COMPETING CONTINUATION	$687,355
														Subtotal = $687,355

Issue Date FY: 2020 ( Subtotal = $693,555 )
2020	2020	SUNNYBROOK RESEARCH INSTITUTE	2075 BAYVIEW AVE	TORONTO	ON	M4N 3M5		CAN	Aging Research	000	4	4/14/2020	NON-COMPETING CONTINUATION	$693,555
														Subtotal = $693,555

Issue Date FY: 2019 ( Subtotal = $593,611 )
2019	2019	SUNNYBROOK RESEARCH INSTITUTE	2075 BAYVIEW AVE	TORONTO	ON	M4N 3M5		CAN	Aging Research	000	3	2/15/2019	NON-COMPETING CONTINUATION	$593,611
														Subtotal = $593,611

Issue Date FY: 2018 ( Subtotal = $697,765 )
2018	2018	SUNNYBROOK RESEARCH INSTITUTE	2075 BAYVIEW AVE	TORONTO	ON	M4N 3M5		CAN	Aging Research	003	2	5/2/2018	NON-COMPETING CONTINUATION	$0
2018	2018	SUNNYBROOK RESEARCH INSTITUTE	2075 BAYVIEW AVE	TORONTO	ON	M4N 3M5		CAN	Aging Research	002	2	4/19/2018	NON-COMPETING CONTINUATION	$69,576
2018	2018	SUNNYBROOK RESEARCH INSTITUTE	2075 BAYVIEW AVE	TORONTO	ON	M4N 3M5		CAN	Aging Research	000	2	2/16/2018	NON-COMPETING CONTINUATION	$626,189
2018	2017	SUNNYBROOK RESEARCH INSTITUTE	2075 BAYVIEW AVE	TORONTO	ON	M4N 3M5		CAN	Aging Research	001	1	3/2/2018	NEW	$2,000
														Subtotal = $697,765

Issue Date FY: 2017 ( Subtotal = $579,117 )
2017	2017	SUNNYBROOK RESEARCH INSTITUTE	2075 BAYVIEW AVE	TORONTO	ON	M4N 3M5		CAN	Aging Research	001	1	6/5/2017	NEW	$103,084
2017	2017	SUNNYBROOK RESEARCH INSTITUTE	2075 BAYVIEW AVE	TORONTO	ON	M4N 3M5		CAN	Aging Research	002	1	6/13/2017	NEW	$1,156
2017	2017	SUNNYBROOK RESEARCH INSTITUTE	2075 BAYVIEW AVE	TORONTO	ON	M4N 3M5		CAN	Aging Research	000	1	3/8/2017	NEW	$474,877
														Subtotal = $579,117

Grand Total All Awards = $2,917,403

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Sleep, Circadian Rhythms, and Mechanisms of Cognitive Decline in the Human Brain

Award Number: R01AG052488

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 03/15/2017

PERIOD OF PERFORMANCE END DATE: 02/28/2025

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