Impact of Sleep Disorders and Disturbed Sleep on Brain Health: A Scientific Statement From the American Heart Association.

Accumulating evidence supports a link between sleep disorders, disturbed sleep, and adverse brain health, ranging from stroke to subclinical cerebrovascular disease to cognitive outcomes, including the development of Alzheimer disease and Alzheimer disease-related dementias. Sleep disorders such as sleep-disordered breathing (eg, obstructive sleep apnea), and other sleep disturbances, as well, some of which are also considered sleep disorders (eg, insomnia, sleep fragmentation, circadian rhythm disorders, and extreme sleep duration), have been associated with adverse brain health. Understanding the causal role of sleep disorders and disturbances in the development of adverse brain health is complicated by the common development of sleep disorders among individuals with neurodegenerative disease. In addition to the role of sleep disorders in stroke and cerebrovascular injury, mechanistic hypotheses linking sleep with brain health and biomarker data (blood-based, cerebrospinal fluid-based, and imaging) suggest direct links to Alzheimer disease-specific pathology. These potential mechanisms and the increasing understanding of the "glymphatic system," and the recognition of the importance of sleep in poststroke recovery, as well, support a biological basis for the indirect (through the worsening of vascular disease) and direct (through specific effects on neuropathology) connections between sleep disorders and brain health. Given promising evidence for the benefits of treatment and prevention, sleep disorders and disturbances represent potential targets for early treatment that may improve brain health more broadly. In this scientific statement, we discuss the evidence supporting an association between sleep disorders and disturbances and poor brain health ranging from stroke to dementia and opportunities for prevention and early treatment.

Cross-sectional associations between neighborhood characteristics, cognition and dementia risk factor burden in middle-aged and older Australians.

Dementia disproportionately affects individuals from disadvantaged backgrounds, including those living in areas of lower neighborhood-level socioeconomic status. It is important to understand whether there are specific neighborhood characteristics associated with dementia risk factors and cognition which may inform dementia risk reduction interventions. We sought to examine whether greenspace, walkability, and crime associated with the cumulative burden of modifiable dementia risk factors and cognition. This was a cross-sectional analysis of 2016-2020 data from the Healthy Brain Project, a population-based cohort of community-dwelling individuals across Australia. Participants were aged 40-70 and free of dementia. Measures included greenspace (greenspace % in the local area, and distance to greenspace, n = 2,181); and intersection density (n = 1,159), and crime (rate of recorded offences; n = 1,159). Outcomes included a modified Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) dementia risk score to index the burden of modifiable vascular dementia risk factors; and composite scores of both memory and attention, derived from the Cogstate Brief Battery. Linear regressions adjusted for age, sex, education, and personal socio-economic status, demonstrated distance to greenspace (b ± SE per 2-fold increase = 0.09 ± 0.03, p =.005) and crime rate (b ± SE per 2-fold increase = 0.07 ± 0.03, p =.018) were associated with higher modified CAIDE. Higher crime was associated with lower memory performance (b ± SE = -0.03 ± 0.01, p =.018). The association between distance to greenspace and modified CAIDE was only present in low-moderate socioeconomic status neighborhoods (p interaction = 0.004). Dementia prevention programs that address modifiable risk factors in midlife should consider the possible role of neighborhood characteristics.

Trends in Intracranial and Cerebral Volumes of Framingham Heart Study Participants Born 1930 to 1970.

Importance: Human brain development and maintenance is under both genetic and environmental influences that likely affect later-life dementia risk. Objective: To examine environmental influences by testing whether time-dependent secular differences occurred in cranial and brain volumes and cortical thickness over birth decades spanning 1930 to 1970. Design, Setting, and Participants: This cross-sectional study used data from the community-based Framingham Heart Study cohort for participants born in the decades 1930 to 1970. Participants did not have dementia or history of stroke and had magnetic resonance imaging (MRI) obtained from March 18, 1999, to November 15, 2019. The final analysis dataset was created in October 2023. Exposure: Years of birth ranging from 1925 to 1968. Main Measures: Cross-sectional analysis of intracranial, cortical gray matter, white matter, and hippocampal volumes as well as cortical surface area and cortical thickness. The secular measure was the decade in which the participant was born. Covariates included age at MRI and sex. Results: The main study cohort consisted of 3226 participants with a mean (SD) age of 57.7 (7.8) years at the time of their MRI. A total of 1706 participants were female (53%) and 1520 (47%) were male. The birth decades ranged from the 1930s to 1970s. Significant trends for larger intracranial, hippocampal, and white matter volumes and cortical surface area were associated with progressive birth decades. Comparing the 1930s birth decade to the 1970s accounted for a 6.6% greater volume (1234 mL; 95% CI, 1220-1248, vs 1321 mL; 95% CI, 1301-1341) for ICV, 7.7% greater volume (441.9 mL; 95% CI, 435.2-448.5, vs 476.3 mL; 95% CI, 467.0-485.7) for white matter, 5.7% greater value (6.51 mL; 95% CI, 6.42-6.60, vs 6.89 mL; 95% CI, 6.77-7.02) for hippocampal volume, and a 14.9% greater value (1933 cm2; 95% CI, 1908-1959, vs 2222 cm2; 95% CI, 2186-2259) for cortical surface area. Repeat analysis applied to a subgroup of 1145 individuals of similar age range born in the 1940s (mean [SD] age, 60.0 [2.8] years) and 1950s (mean [SD] age, 59.0 [2.8] years) resulted in similar findings. Conclusion and Relevance: In this study, secular trends for larger brain volumes suggested improved brain development among individuals born between 1930 and 1970. Early life environmental influences may explain these results and contribute to the declining dementia incidence previously reported in the Framingham Heart Study cohort.

Association of the Sleep Regularity Index With Incident Dementia and Brain Volume.

BACKGROUND AND OBJECTIVES: Irregular sleep may increase the risk of cardiometabolic conditions, but its association with incident dementia is unclear. The aim of this study was to assess the association between sleep regularity, that is, the day-to-day consistency in sleep-wake patterns and the risk of incident dementia and related brain MRI endophenotypes. METHODS: We used Cox proportional hazard models to investigate the relationships between sleep regularity and incident dementia in 88,094 UK Biobank participants. The sleep regularity index (SRI) was calculated as the probability of being in the same state (asleep/awake) at any 2 time points 24 hours apart, averaged over 7 days of accelerometry. RESULTS: The mean age of the sample was 62 years (SD = 8), 56% were women, and the median SRI was 60 (SD = 10). There were 480 cases of incident dementia over a median 7.2 years of follow-up. Following adjustments for demographic, clinical, and genetic confounders (APOE ε4), there was a nonlinear association between the SRI and dementia hazard (p [global test of spline term] < 0.001) with hazard ratios (HRs) following a U-shape pattern. HRs, relative to the median SRI, were 1.53 (95% CI 1.24-1.89) for participants with SRI at the 5th percentile (SRI = 41) and 1.16 (95% CI 0.89-1.50) for those with SRI at the 95th percentile (SRI = 71). In a subset with brain MRI (n = 15,263), gray matter and hippocampal volume tended to be lowest at the extremes of the SRI. DISCUSSION: Sleep regularity displayed a U-shaped association with risk of incident dementia. Irregular sleep may represent a novel dementia risk factor.

Association of Sleep Duration and Change Over Time With Imaging Biomarkers of Cerebrovascular, Amyloid, Tau, and Neurodegenerative Pathology.

BACKGROUND AND OBJECTIVES: Both short and long sleep duration were previously associated with incident dementia, but underlying mechanisms remain unclear. We evaluated how self-reported sleep duration and its change over time associate with (A)myloid, (T)au, (N)eurodegeneration, and (V)ascular neuroimaging markers of Alzheimer disease. METHODS: Two Framingham Heart Study overlapping samples were studied: participants who underwent 11C-Pittsburg Compound B amyloid and 18F-flortaucipir tau PET imaging and participants who underwent an MRI. MRI metrics estimated neurodegeneration (total brain volume) and cerebrovascular injuries (white matter hyperintensities [WMHs] volume, covert brain infarcts, free-water [FW] fraction). Self-reported sleep duration was assessed and split into categories both at the time of neuroimaging testing and approximately 13 years before: short ≤6 hours. average 7-8 hours, and long ≥9 hours. Logistic and linear regression models were used to examine sleep duration and neuroimaging metrics. RESULTS: The tested cohort was composed of 271 participants (age 53.6 ± 8.0 years; 51% male) in the PET imaging sample and 2,165 participants (age 61.3 ± 11.1 years; 45% male) in the MRI sample. No fully adjusted association was observed between cross-sectional sleep duration and neuroimaging metrics. In fully adjusted models compared with consistently sleeping 7-8 hours, groups transitioning to a longer sleep duration category over time had higher FW fraction (short to average ß [SE] 0.0062 [0.0024], p = 0.009; short to long ß [SE] 0.0164 [0.0076], p = 0.031; average to long ß [SE] 0.0083 [0.0022], p = 0.002), and those specifically going from average to long sleep duration also had higher WMH burden (ß [SE] 0.29 [0.11], p = 0.007). The opposite associations (lower WMH and FW) were observed in participants consistently sleeping ≥9 hours as compared with people consistently sleeping 7-8 hours in fully adjusted models (ß [SE] -0.43 [0.20], p = 0.028; ß [SE] -0.019 [0.004], p = 0.020). Each hour of increasing sleep (continuous, ß [SE] 0.12 [0.04], p = 0.003; ß [SE] 0.002 [0.001], p = 0.021) and extensive increase in sleep duration (≥2 hours vs 0 ± 1 hour change; ß [SE] 0.24 [0.10], p = 0.019; ß [SE] 0.0081 [0.0025], p = 0.001) over time was associated with higher WMH burden and FW fraction in fully adjusted models. Sleep duration change was not associated with PET amyloid or tau outcomes. DISCUSSION: Longer self-reported sleep duration over time was associated with neuroimaging biomarkers of cerebrovascular pathology as evidenced by higher WMH burden and FW fraction. A longer sleep duration extending over time may be an early change in the neurodegenerative trajectory.

Associations of Plasma Tau with Amyloid and Tau PET: Results from the Community-Based Framingham Heart Study.

Background: Associations of plasma total tau levels with future risk of AD have been described. Objective: To examine the extent to which plasma tau reflects underlying AD brain pathology in cognitively healthy individuals. Methods: We examined cross-sectional associations of plasma total tau with 11C-Pittsburgh Compound-B (PiB)-PET and 18F-Flortaucipir (FTP)-PET in middle-aged participants at the community-based Framingham Heart Study. Results: Our final sample included 425 participants (mean age 57.6± 9.9, 50% F). Plasma total tau levels were positively associated with amyloid-ß deposition in the precuneus region (ß±SE, 0.11±0.05; p = 0.025). A positive association between plasma total tau and tau PET in the rhinal cortex was suggested in participants with higher amyloid-PET burden and in APOEɛ4 carriers. Conclusions: Our study highlights that plasma total tau is a marker of amyloid deposition as early as in middle-age.

Association of Plasma YKL-40 With MRI, CSF, and Cognitive Markers of Brain Health and Dementia.

BACKGROUND AND OBJECTIVES: Higher YKL-40 levels in the CSF are a known biomarker of brain inflammation. We explored the utility of plasma YKL-40 as a biomarker for accelerated brain aging and dementia risk. METHODS: We performed cross-sectional and prospective analyses of 4 community-based cohorts in the United States or Europe: the Age, Gene/Environment Susceptibility-Reykjavik Study, Atherosclerosis Risk in the Communities study, Coronary Artery Risk Development in Young Adults study, and Framingham Heart Study (FHS). YKL-40 was measured from stored plasma by a single laboratory using Mesoscale Discovery with levels log transformed and standardized within each cohort. Outcomes included MRI total brain volume, hippocampal volume, and white matter hyperintensity volume (WMHV) as a percentage of intracranial volume, a general cognitive composite derived from neuropsychological testing (SD units [SDU]), and the risk of incident dementia. We sought to replicate associations with dementia in the clinic-based ACE csf cohort, which also had YKL-40 measured from the CSF. RESULTS: Meta-analyses of MRI outcomes included 6,558 dementia-free participants, and for analysis of cognition, 6,670. The blood draw preceded MRI/cognitive assessment by up to 10.6 years across cohorts. The mean ages ranged from 50 to 76 years, with 39%-48% male individuals. In random-effects meta-analysis of study estimates, each SDU increase in log-transformed YKL-40 levels was associated with smaller total brain volume (ß = -0.33; 95% CI -0.45 to -0.22; p < 0.0001) and poorer cognition (ß = -0.04; 95% CI -0.07 to -0.02; p < 0.01), following adjustments for demographic variables. YKL-40 levels did not associate with hippocampal volume or WMHV. In the FHS, each SDU increase in log YKL-40 levels was associated with a 64% increase in incident dementia risk over a median of 5.8 years of follow-up, following adjustments for demographic variables (hazard ratio 1.64; 95% CI 1.25-2.16; p < 0.001). In the ACE csf cohort, plasma and CSF YKL-40 were correlated (r = 0.31), and both were associated with conversion from mild cognitive impairment to dementia, independent of amyloid, tau, and neurodegeneration status. DISCUSSION: Higher plasma YKL-40 levels were associated with lower brain volume, poorer cognition, and incident dementia. Plasma YKL-40 may be useful for studying the association of inflammation and its treatment on dementia risk.

Imaging the neurovascular unit in health and neurodegeneration: a scoping review of interdependencies between MRI measures.

The neurovascular unit (NVU) is a complex structure that facilitates nutrient delivery and metabolic waste clearance, forms the blood-brain barrier (BBB), and supports fluid homeostasis in the brain. The integrity of NVU subcomponents can be measured in vivo using magnetic resonance imaging (MRI), including quantification of enlarged perivascular spaces (ePVS), BBB permeability, cerebral perfusion and extracellular free water. The breakdown of NVU subparts is individually associated with aging, pathology, and cognition. However, how these subcomponents interact as a system, and how interdependencies are impacted by pathology remains unclear. This systematic scoping review identified 26 studies that investigated the inter-relationships between multiple subcomponents of the NVU in nonclinical and neurodegenerative populations using MRI. A further 112 studies investigated associations between the NVU and white matter hyperintensities (WMH). We identify two putative clusters of NVU interdependencies: a 'vascular' cluster comprising BBB permeability, perfusion and basal ganglia ePVS; and a 'fluid' cluster comprising ePVS, free water and WMH. Emerging evidence suggests that subcomponent coupling within these clusters may be differentially related to aging, neurovascular injury or neurodegenerative pathology.