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.

Association Between Slow-Wave Sleep Loss and Incident Dementia.

Importance: Slow-wave sleep (SWS) supports the aging brain in many ways, including facilitating the glymphatic clearance of proteins that aggregate in Alzheimer disease. However, the role of SWS in the development of dementia remains equivocal. Objective: To determine whether SWS loss with aging is associated with the risk of incident dementia and examine whether Alzheimer disease genetic risk or hippocampal volumes suggestive of early neurodegeneration were associated with SWS loss. Design, Setting, and Participants: This prospective cohort study included participants in the Framingham Heart Study who completed 2 overnight polysomnography (PSG) studies in the time periods 1995 to 1998 and 2001 to 2003. Additional criteria for individuals in this study sample were an age of 60 years or older and no dementia at the time of the second overnight PSG. Data analysis was performed from January 2020 to August 2023. Exposure: Changes in SWS percentage measured across repeated overnight sleep studies over a mean of 5.2 years apart (range, 4.8-7.1 years). Main Outcome: Risk of incident all-cause dementia adjudicated over 17 years of follow-up from the second PSG. Results: From the 868 Framingham Heart Study participants who returned for a second PSG, this cohort included 346 participants with a mean age of 69 years (range, 60-87 years); 179 (52%) were female. Aging was associated with SWS loss across repeated overnight sleep studies (mean [SD] change, -0.6 [1.5%] per year; P < .001). Over the next 17 years of follow-up, there were 52 cases of incident dementia. In Cox regression models adjusted for age, sex, cohort, positivity for at least 1 APOE ε4 allele, smoking status, sleeping medication use, antidepressant use, and anxiolytic use, each percentage decrease in SWS per year was associated with a 27% increase in the risk of dementia (hazard ratio, 1.27; 95% CI, 1.06-1.54; P = .01). SWS loss with aging was accelerated in the presence of Alzheimer disease genetic risk (ie, APOE ε4 allele) but not hippocampal volumes measured proximal to the first PSG. Conclusions and Relevance: This cohort study found that slow-wave sleep percentage declined with aging and Alzheimer disease genetic risk, with greater reductions associated with the risk of incident dementia. These findings suggest that SWS loss may be a modifiable dementia risk factor.

Sleep Architecture, Obstructive Sleep Apnea, and Cognitive Function in Adults.

Importance: Good sleep is essential for health, yet associations between sleep and dementia risk remain incompletely understood. The Sleep and Dementia Consortium was established to study associations between polysomnography (PSG)-derived sleep and the risk of dementia and related cognitive and brain magnetic resonance imaging endophenotypes. Objective: To investigate association of sleep architecture and obstructive sleep apnea (OSA) with cognitive function in the Sleep and Dementia Consortium. Design, Setting, and Participants: The Sleep and Dementia Consortium curated data from 5 population-based cohorts across the US with methodologically consistent, overnight, home-based type II PSG and neuropsychological assessments over 5 years of follow-up: the Atherosclerosis Risk in Communities study, Cardiovascular Health Study, Framingham Heart Study (FHS), Osteoporotic Fractures in Men Study, and Study of Osteoporotic Fractures. Sleep metrics were harmonized centrally and then distributed to participating cohorts for cohort-specific analysis using linear regression; study-level estimates were pooled in random effects meta-analyses. Results were adjusted for demographic variables, the time between PSG and neuropsychological assessment (0-5 years), body mass index, antidepressant use, and sedative use. There were 5946 participants included in the pooled analyses without stroke or dementia. Data were analyzed from March 2020 to June 2023. Exposures: Measures of sleep architecture and OSA derived from in-home PSG. Main Outcomes and Measures: The main outcomes were global cognitive composite z scores derived from principal component analysis, with cognitive domains investigated as secondary outcomes. Higher scores indicated better performance. Results: Across cohorts, 5946 adults (1875 females [31.5%]; mean age range, 58-89 years) were included. The median (IQR) wake after sleep onset time ranged from 44 (27-73) to 101 (66-147) minutes, and the prevalence of moderate to severe OSA ranged from 16.9% to 28.9%. Across cohorts, higher sleep maintenance efficiency (pooled ß per 1% increase, 0.08; 95% CI, 0.03 to 0.14; P < .01) and lower wake after sleep onset (pooled ß per 1-min increase, -0.07; 95% CI, -0.13 to -0.01 per 1-min increase; P = .02) were associated with better global cognition. Mild to severe OSA (apnea-hypopnea index [AHI] ≥5) was associated with poorer global cognition (pooled ß, -0.06; 95% CI, -0.11 to -0.01; P = .01) vs AHI less than 5; comparable results were found for moderate to severe OSA (pooled ß, -0.06; 95% CI, -0.11 to -0.01; P = .02) vs AHI less than 5. Differences in sleep stages were not associated with cognition. Conclusions and Relevance: This study found that better sleep consolidation and the absence of OSA were associated with better global cognition over 5 years of follow-up. These findings suggest that the role of interventions to improve sleep for maintaining cognitive function requires investigation.

The prevalence, correlation, and co-occurrence of neuropathology in old age: harmonisation of 12 measures across six community-based autopsy studies of dementia.

BACKGROUND: Population-based autopsy studies provide valuable insights into the causes of dementia but are limited by sample size and restriction to specific populations. Harmonisation across studies increases statistical power and allows meaningful comparisons between studies. We aimed to harmonise neuropathology measures across studies and assess the prevalence, correlation, and co-occurrence of neuropathologies in the ageing population. METHODS: We combined data from six community-based autopsy cohorts in the US and the UK in a coordinated cross-sectional analysis. Among all decedents aged 80 years or older, we assessed 12 neuropathologies known to be associated with dementia: arteriolosclerosis, atherosclerosis, macroinfarcts, microinfarcts, lacunes, cerebral amyloid angiopathy, Braak neurofibrillary tangle stage, Consortium to Establish a Registry for Alzheimer's disease (CERAD) diffuse plaque score, CERAD neuritic plaque score, hippocampal sclerosis, limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), and Lewy body pathology. We divided measures into three groups describing level of confidence (low, moderate, and high) in harmonisation. We described the prevalence, correlations, and co-occurrence of neuropathologies. FINDINGS: The cohorts included 4354 decedents aged 80 years or older with autopsy data. All cohorts included more women than men, with the exception of one study that only included men, and all cohorts included decedents at older ages (range of mean age at death across cohorts 88·0-91·6 years). Measures of Alzheimer's disease neuropathological change, Braak stage and CERAD scores, were in the high confidence category, whereas measures of vascular neuropathologies were in the low (arterioloscerosis, atherosclerosis, cerebral amyloid angiopathy, and lacunes) or moderate (macroinfarcts and microinfarcts) categories. Neuropathology prevalence and co-occurrence was high (2443 [91%] of 2695 participants had more than one of six key neuropathologies and 1106 [41%] of 2695 had three or more). Co-occurrence was strongly but not deterministically associated with dementia status. Vascular and Alzheimer's disease features clustered separately in correlation analyses, and LATE-NC had moderate associations with Alzheimer's disease measures (eg, Braak stage ρ=0·31 [95% CI 0·20-0·42]). INTERPRETATION: Higher variability and more inconsistency in the measurement of vascular neuropathologies compared with the measurement of Alzheimer's disease neuropathological change suggests the development of new frameworks for the measurement of vascular neuropathologies might be helpful. Results highlight the complexity and multi-morbidity of the brain pathologies that underlie dementia in older adults and suggest that prevention efforts and treatments should be multifaceted. FUNDING: Gates Ventures.

Association of Red Blood Cell Omega-3 Fatty Acids With MRI Markers and Cognitive Function in Midlife: The Framingham Heart Study.

BACKGROUND AND OBJECTIVES: Diet may be a key contributor to brain health in midlife. In particular, Omega-3 fatty acids have been related to better neurological outcomes in older adults. However, studies focusing on midlife are lacking. We investigated the cross-sectional association of red blood cell (RBC) Omega-3 fatty acid concentrations with MRI and cognitive markers of brain aging in a community-based sample of predominantly middle-aged adults, and further explore effect modification by APOE genotype. METHODS: We included participants from the Third-Generation and Omni 2 cohorts of the Framingham Heart Study attending their second examination. Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) concentrations were measured from RBC using gas chromatography, and the Omega-3 index was calculated as EPA + DHA. We used linear regression models to relate Omega-3 fatty acid concentrations to brain MRI measures (i.e., total brain, total gray matter, hippocampal, and white matter hyperintensity volumes) and cognitive function (i.e., episodic memory, processing speed, executive function, and abstract reasoning) adjusting for potential confounders. We further tested for interactions between omega-3 fatty acid levels and APOE genotype (e4 carrier vs. non-carrier) on MRI and cognitive outcomes. RESULTS: We included 2,183 dementia- and stroke-free participants (mean age 46 years, 53% women, 22% APOE-e4 carriers). In multivariable models, higher Omega-3 index was associated with larger hippocampal volumes (standard deviation unit beta ±standard error; 0.003 ±0.001, p=0.04), and better abstract reasoning (0.17 ±0.07, p=0.013). Similar results were obtained for DHA or EPA concentrations individually. Stratification by APOE-e4 status showed associations between higher DHA concentrations or Omega-3 index and larger hippocampal volumes in APOE-e4 non-carriers, whereas higher EPA concentrations were related to better abstract reasoning in APOE-e4 carriers. Finally, higher levels of all Omega-3 predictors were related to lower white matter hyperintensity burden but only in APOE-e4 carriers. DISCUSSION: Our results, albeit exploratory, suggest that higher Omega-3 fatty acid concentrations are related to better brain structure and cognitive function in a predominantly middle-aged cohort free of clinical dementia. These associations differed by APOE genotype, suggesting potentially different metabolic patterns by APOE status. Additional studies in middle-age populations are warranted to confirm these findings.

Self-reported sleepiness associates with greater brain and cortical volume and lower prevalence of ischemic covert brain infarcts in a community sample.

STUDY OBJECTIVES: We evaluated if self-reported sleepiness was associated with neuroimaging markers of brain aging and ischemic damage in a large community-based sample. METHODS: Participants from the Framingham Heart Study Offspring cohort (n = 468, 62.5 ± 8.7 years old, 49.6%M) free of dementia, stroke, and neurological diseases, completed sleep questionnaires and polysomnography followed by magnetic resonance imaging (MRI), 3 years later on average. We used linear and logistic regression models to evaluate the associations between Epworth Sleepiness Scale (ESS) scores and total brain, cortical and subcortical gray matter, and white matter hyperintensities volumes, and the presence of covert brain infarcts. RESULTS: Higher sleepiness scores were associated with larger total brain volume, greater cortical gray matter volume, and a lower prevalence of covert brain infarcts, even when adjusting for a large array of potential confounders, including demographics, sleep profiles and disorders, organic health diseases, and proxies for daytime cognitive and physical activities. Interactions indicated that more sleepiness was associated with larger cortical gray matter volume in men only and in APOE ε4 noncarriers, whereas a trend for smaller cortical gray matter volume was observed in carriers. In longitudinal analyses, those with stable excessive daytime sleepiness over time had greater total brain and cortical gray matter volumes, whereas baseline sleepiness scores were not associated with subsequent atrophy or cognitive decline. CONCLUSION: Our findings suggest that sleepiness is not necessarily a marker of poor brain health when not explained by diseases or sleep debt and sleep disorders. Rather, sleepiness could be a marker of preserved sleep-regulatory processes and brain health in some cases.

Insomnia symptom severity and cognitive performance: Moderating role of APOE genotype.

INTRODUCTION: We evaluated whether insomnia symptom severity was associated with cognitive function, and whether this relationship was modified by biomarkers associated with Alzheimer's disease risk. METHODS: We examined insomnia symptoms and neuropsychological performance 3.4 years later in 511 dementia-free Framingham Heart Study participants (62.65 ± 8.7 years, 50.9% male). Additionally, we explored insomnia symptoms combined with self-reported short habitual sleep duration and effect modification by apolipoprotein E (APOE) ε4 allele status. RESULTS: More severe insomnia symptoms were associated with lower performance on global cognition, and immediate and delayed Logical Memory recall, especially when insomnia symptoms were combined with short sleep duration. The association between insomnia symptoms and poorer memory recall was more pronounced in APOE ε4 allele carriers. DISCUSSION: Insomnia symptom severity was associated with worse subsequent global cognitive and memory performance, which was especially apparent in APOE ε4 allele carriers, suggesting that poor sleep might be particularly detrimental when the brain is already vulnerable to neurodegeneration.

Microwave flash pyrolysis.

In a microwave reactor, graphite heats rapidly to high surface temperatures; applications of graphite thermal "sensitization" have been described previously. We report here that microwave thermal sensitization with graphite, carbon nanotubes, or silicon carbide can be used to carry out reactions more typically accomplished by flash vacuum pyrolysis (FVP) and which usually require temperatures much higher than the nominal limit of a microwave reactor. The graphite-sensitized microwave reaction of azulene in the solid phase at temperatures of 100 to 300 degrees C affords rapid rearrangement to naphthalene, a reaction typically observed by FVP at 700-900 degrees C. Multiwall carbon nanotubes give similar results when used as a thermal sensitizer. Other graphite-sensitized reactions that we have observed include the following: conversion of 2-ethynylbiphenyl to phenanthrene, fragmentation of phthalic anhydride to benzyne, cleavage of iodobenzene to phenyl radical, aryl-aryl bond cleavage, and a variety of cycloaromatizations. An advantage is seen for less volatile substrates. Rearrangement of azulene and generation of benzyne from phthalic anhydride have also been observed on powdered silicon carbide. Because of the high temperature, rapid heating, and frequent ejection of material from the irradiation zone, we refer to this general method as microwave flash pyrolysis (MFP).