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Refereed/Peer-reviewed 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.

Background and ObjectivesDiet may be a key contributor to brain health in midlife. In particular, omega-3 fatty acids have been related to better neurologic 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 byAPOEgenotype.MethodsWe 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 andAPOEgenotype (e4 carrier vs noncarrier) on MRI and cognitive outcomes.ResultsWe included 2,183 dementia-free and stroke-free participants (mean age of 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= 0.013) and better abstract reasoning (0.17 ± 0.07,p= 0.013). Similar results were obtained for DHA or EPA concentrations individually. Stratification byAPOE-e4 status showed associations between higher DHA concentrations or Omega-3 index and larger hippocampal volumes inAPOE-e4 noncarriers, whereas higher EPA concentrations were related to better abstract reasoning inAPOE-e4 carriers. Finally, higher levels of all omega-3 predictors were related to lower white matter hyperintensity burden but only inAPOE-e4 carriers.DiscussionOur 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 byAPOEgenotype, suggesting potentially different metabolic patterns by APOE status. Additional studies in middle-aged populations are warranted to confirm these findings.

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.

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.

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).