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Principal Investigator: Shaun M Purcell
Organization: BRIGHAM AND WOMEN'S HOSPITAL
Fiscal Year: 2024
Award: $1,321,590
Funding agency: National Institute on Aging
As the population has aged, there has been a staggering increase in the prevalence and morbidity of cognitive
impairment and Alzheimer's disease (AD) related dementias (ADRD): by 2050 the number of people in the U.S.
with ADRD will triple to 13.8 million, and associated health care costs will exceed $1.1 trillion annually.
Combinations of genetic, lifestyle and environmental factors appear to increase risk for ADRD through age-
related changes in neuronal processes that lead to progressive accumulation of amyloid-beta (Aß) and tau. While
there is growing recognition that disturbed sleep and circadian disturbances may accelerate Aß accumulation
and cognitive decline, the literature is inconclusive regarding the causal vs non-causal role of specific sleep
disturbances and has not addressed whether nocturnal hypertension (a modifiable target) mediates sleep-related
cognitive outcomes. We will exploit the marked inter-individual variability in many sleep measures, as well as
substantial intra-individual changes over time to develop a longitudinal framework to better approach questions
of causality. We propose to leverage the comprehensive sleep phenotyping performed from 2010-2013 (MESA-
SLEEP; Exam 5), along with ongoing and newly proposed data to be collected in the MESA MIND study, which
includes state-of-the-art cognitive, neuropsychiatric, and brain imaging studies in a sample of MESA participants
studied at 2 time points 2.5 years apart (2019-2023) to efficiently and uniquely address critical research gaps.
While the MESA MIND study addresses the role of mid- and later-life vascular disease as a risk factor for ADRD,
it does not address the potential contributory or mediating roles of sleep and circadian disorders. We therefore
propose to efficiently expand the MESA MIND study second exam (2021-2023) to include overnight state-of-the-
art polysomnography, 7-day actigraphy, and for the first time in MESA, 24-hour blood pressure recordings,
aiming to recruit 1800 of the 2000 participants targeted for that exam. We will generate advanced quantitative
metrics of sleep and circadian rhythm to characterize the evolution of sleep disturbances over critical aging
periods. These measurements will be incorporated into longitudinal assessments of cognition in order to define
the temporal associations between sleep disturbances and cognitive impairment, and thus define which sleep
disturbances and metrics are antecedent factors for cognitive impairment. We will evaluate whether sleep
measured 8 years prior to brain imaging, as well as trajectories of sleep change, predict neurodegeneration,
cerebral vascular disease and AD brain biomarkers as measured by repeated brain MRI and PET imaging
(performed as part of the MESA MIND Study). We also will assess the role of blood pressure variability and
nocturnal hypertension as a mediating pathway linking sleep disturbance and cognition/AD susceptibility. We
will explore differences in associations between men and women and individuals of different race/ethnic
backgrounds. The study has large potential impact given that sleep disturbances and nocturnal hypertension are
modifiable targets. The study also will inform gender-appropriate risk stratification approaches.
Terms: <65 and older><65 or older><65 years of age and older><65 years of age or more><65 years of age or older><65+ years><65+ years old><> 65 years><AD dementia><AD related dementia><ADRD><Acceleration><Address><Age-associated cognitive decline><Age-associated memory impairment><Age-related cognitive decline><Aged 65 and Over><Aging><Alzheimer Type Dementia><Alzheimer disease dementia><Alzheimer risk factor><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimer's and related dementias><Alzheimer's biomarker><Alzheimer's brain><Alzheimer's disease and related dementia><Alzheimer's disease and related disorders><Alzheimer's disease biological marker><Alzheimer's disease brain><Alzheimer's disease or a related dementia><Alzheimer's disease or a related disorder><Alzheimer's disease or related dementia><Alzheimer's disease related dementia><Alzheimer's disease risk><Alzheimers Dementia><Alzheimer’s biological marker><Alzheimer’s disease biomarker><Ambulatory Blood Pressure Monitoring><Amentia><American><Ammon Horn><Aβ burden><Benign senescent forgetfulness><Biological Markers><Blood Pressure><Blood Vessels><Brain><Brain Nervous System><Brain Vascular Disorders><Brain imaging><Causality><Cerebral small vessel disease><Cerebrovascular Disease><Cerebrovascular Disorders><Cerebrum><Circadian Dysregulation><Circadian Rhythms><Cognition><Cognitive><Cognitive Disturbance><Cognitive Impairment><Cognitive aging><Cognitive decline><Cognitive function abnormal><Cornu Ammonis><Data><Data Collection><Data Set><Dementia><Diathesis><Differences between sexes><Differs between sexes><Disease><Disease Marker><Disease susceptibility><Disorder><Disturbance in cognition><EEG><Electroencephalogram><Electroencephalography><Encephalon><Environmental Factor><Environmental Risk Factor><Ethnic Origin><Ethnicity><Etiology><Evolution><Family><Gender><Genetic><Health><Health Care Costs><Health Costs><Healthcare Costs><Hippocampus><Hour><Hypoxia><Hypoxic><Impaired cognition><Incidence><Individual><Individual Differences><Intervention><Intervention Strategies><Intracranial Vascular Diseases><Intracranial Vascular Disorders><Knowledge><Leanness><Link><Literature><Long-term cohort><Longitudinal cohort><Longterm cohort><MR Imaging><MR Tomography><MRI><MRIs><MT-bound tau><Magnetic Resonance Imaging><Measurement><Measures><Mediating><Mediator><Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance><Morbidity><Morbidity - disease rate><Multi-Ethnic Study of Atherosclerosis><Multiomic Data><NMR Imaging><NMR Tomography><Nerve Cells><Nerve Degeneration><Nerve Unit><Neural Cell><Neurocognitive><Neurocyte><Neuron Degeneration><Neurons><Night-time Hypertension><Nocturnal Hypertension><Nuclear Magnetic Resonance Imaging><Nyctohemeral Rhythm><Outcome><Oxygen Deficiency><PET><PET Scan><PET imaging><PETSCAN><PETT><Participant><Pathologic><Pathway interactions><Pattern><Perfusion><Personal Satisfaction><Persons><Phenotype><Physiology><Pittsburgh Compound-B><Polysomnography><Population><Positron Emission Tomography Medical Imaging><Positron Emission Tomography Scan><Positron-Emission Tomography><Predisposition><Prevalence><Primary Senile Degenerative Dementia><Process><Public Health><Race><Races><Rad.-PET><Research><Risk><Risk Factors><Role><Sampling><Sex Differences><Sexual differences><Sleep><Sleep Apnea><Sleep Apnea Syndromes><Sleep Hypopnea><Sleep Monitoring><Sleep disturbances><Sleep-Disordered Breathing><Somnography><Source><Susceptibility><Thinness><Time><Twenty-Four Hour Rhythm><Vascular Diseases><Vascular Disorder><White Matter Disease><Woman><Zeugmatography><a-beta burden><aberrant sleep><abeta accumulation><abeta aggregation><abeta burden><abeta deposition><above age 65><actigraph><actigraphy><after age 65><age 65 and greater><age 65 and older><age 65 or older><age > 65><age associated><age associated alterations><age associated changes><age associated memory decline><age correlated><age correlated alterations><age correlated changes><age dependent><age dependent alterations><age dependent changes><age linked><age of 65 years onward><age related><age related alterations><age related changes><age related cognitive deficit><age related cognitive impairment><age related memory dysfunction><age specific><age specific alterations><age specific changes><age-induced cognitive decline><age-related decline in cognition><age-related decline in cognitive function><aged><aged 65 and greater><aged 65+><aged ≥65><alterations with age><alzheimer risk><amyloid beta accumulation><amyloid beta aggregation><amyloid beta deposition><amyloid burden><amyloid β accumulation><amyloid β aggregation><amyloid β deposition><arterial stiffening><arterial stiffness><artery stiffening><artery stiffness><aβ accumulation><aβ aggregation><aβ deposition><beta amyloid burden><bio-markers><biologic marker><biomarker><blood pressure variability><blood vessel disorder><brain MR imaging><brain MRI><brain based><brain health><brain magnetic resonance imaging><brain vascular disease><brain vascular dysfunction><brain visualization><cardiometabolic><cardiometabolism><cardiovascular disease risk><cardiovascular disorder risk><causation><cerebral><cerebral MR imaging><cerebral MRI><cerebral magnetic resonance imaging><cerebral small vessel disorder><cerebral vascular disease><cerebral vascular dysfunction><cerebrovascular dysfunction><changes with age><circadian><circadian abnormality><circadian disruption><circadian disturbance><circadian dysfunction><circadian impairment><circadian process><cognitive change><cognitive dysfunction><cognitive loss><cognitive performance><critical period><daily biorhythm><dementia risk><differences due to race><differences in race><differs by race><differs in race><disease causation><disrupted sleep><disturbed sleep><environmental risk><ethnic difference><ethnic diversity><ethnically diverse><ethnicity difference><hippocampal><human old age (65+)><imaging biomarker><imaging marker><imaging study><imaging-based biological marker><imaging-based biomarker><imaging-based marker><impaired sleep><inter-individual variability><inter-individual variation><interindividual variability><interindividual variation><interventional strategy><intracranial vascular dysfunction><irregular sleep><late life><liability to disease><life-style factor><lifestyle factors><ligand PIB><men><metabolic phenotype><metabotype><microtubule bound tau><microtubule-bound tau><mid life><mid-life><middle age><middle aged><midlife><mild cognitive disorder><mild cognitive impairment><multiple omic data><neural degeneration><neurodegeneration><neurodegenerative><neurological degeneration><neuronal><neuronal degeneration><neuropsychiatric><neuropsychiatry><novel><old age><over 65 years><pathway><polysomnographic><positron emission tomographic (PET) imaging><positron emission tomographic imaging><positron emitting tomography><primary degenerative dementia><quality of sleep><race based differences><race differences><race related differences><racial><racial background><racial difference><racial origin><racially different><recruit><risk factor for dementia><risk for dementia><risk mitigation><risk stratification><senile dementia of the Alzheimer type><sex based differences><sex-dependent differences><sex-related differences><sex-specific differences><sleep disruption><sleep dysregulation><sleep health><sleep hygiene><sleep measurement><sleep physiology><sleep polysomnography><sleep quality><sleep-related breathing disorder><social role><stratify risk><tau><tau Proteins><tau factor><temporal measurement><temporal resolution><time measurement><uptake><vascular><vascular dysfunction><vascular risk factor><vasculopathy><well-being><wellbeing><β-amyloid burden><βamyloid burden><τ Proteins><≥65 years>