Poorer subjective sleep quality was associated with reduced total cortical and regional frontal lobe volumes independent of comorbid psychiatric conditions. Future work will be needed to examine if effective treatment of disturbed sleep leads to improved structural and functional integrity of the frontal lobes.

IMPORTANCE Disrupted sleep commonly occurs with progressing neurodegenerative disease. Large, well-characterized neuroimaging studies of cognitively unimpaired adults are warranted to clarify the magnitude and onset of the association between sleep and emerging β-amyloid (Aβ) pathology. OBJECTIVE To evaluate the associations between daytime and nighttime sleep duration with regional Aβ pathology in older cognitively unimpaired adults. DESIGN, SETTING, AND PARTICIPANTS In this cross-sectional study, screening data were collected between April 1, 2014, and December 31, 2017, from healthy, cognitively unimpaired adults 65 to 85 years of age who underwent florbetapir F 18 positron emission tomography (PET), had APOE genotype information, scored between 25 and 30 on the Mini-Mental State Examination, and had a Clinical Dementia Rating of 0 for the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease (A4) Study. Data analysis was performed from December 1, 2019, to May 10, 2021. EXPOSURES Self-reported daytime and nighttime sleep duration. MAIN OUTCOMES AND MEASURES Regional Aβ pathology, measured by florbetapir PET standardized uptake value ratio. RESULTS Amyloid PET and sleep duration information was acquired on 4425 cognitively unimpaired participants (mean [SD] age, 71.3 [4.7] years; 2628 [59.4%] female; 1509 [34.1%] tested Aβ positive).Each additional hour of nighttime sleep was associated with a 0.005 reduction of global Aβ standardized uptake value ratio (F 1, 4419 = 5.0; P = .03), a 0.009 reduction of medial orbitofrontal Aβ (F 1, 4419 = 17.4; P < .001), and a 0.011 reduction of anterior cingulate Aβ (F 1, 4419 = 15.9; P < .001). When restricting analyses to participants who tested Aβ negative, nighttime sleep was associated with a 0.006 reduction of medial orbitofrontal Aβ (F 1,2910 = 16.9; P < .001) and a 0.005 reduction of anterior cingulate Aβ (F 1,2910 = 7.6; P = .03). Daytime sleep was associated with a 0.013 increase of precuneus Aβ (F 1,2910 = 7.3; P = .03) and a 0.024 increase of posterior cingulate Aβ (F 1,2910 = 14.2; P = .001) in participants who tested Aβ negative. CONCLUSIONS AND RELEVANCEIn this cross-sectional study, the increased risk of Aβ deposition with reduced nighttime sleep duration occurred early, before cognitive impairment or significant Aβ deposition. Daytime sleep may be associated with an increase in risk for early Aβ accumulation and did not appear to be corrective for loss of nighttime sleep, demonstrating a circadian rhythm dependence of sleep in preventing Aβ accumulation. Treatments that improve sleep may reduce early Aβ accumulation and aid in delaying the onset of cognitive dysfunction associated with early Alzheimer disease.

These results extend existing data on sleep duration and cognition across the lifespan by combining in a single study the results from four specific cognitive tests, both younger and older adults, and four self-reported risk factors for cognitive impairment. Longitudinal studies with biomarkers should be undertaken to determine whether causal mechanisms, such as inflammation or amyloid buildup, account for these associations.

These findings challenge the hypothesis that deteriorating cognitive performance with long sleep duration is driven by medical comorbidities associated with aging. Further, these data are consistent with an optimal dose model of sleep and suggest that the model for the homeostatic recovery of cognitive function as a function of sleep duration should incorporate a curvilinear decline with longer duration sleep, indicating that there may be a cost to increased sleep. Replication and further research is essential for clarifying the sleep duration-cognition relationship in youth and adults of all ages.

Background Reduced cerebrospinal fluid (CSF) α-synuclein has been described in synucleinopathies, including dementia with Lewy bodies (DLB). Common symptoms of DLB include visual hallucinations and visuospatial and executive deficits. Co-occurrence of Lewy body pathology is common in Alzheimer’s disease (AD) patients, but it is unknown if reduced CSF α-synuclein is associated with Lewy body-like symptomatology in AD. Objective Determine associations between CSF α-synuclein and Lewy body-like symptomatology. Methods We included 73 controls (NC), 121 mild cognitive impairment (MCI) patients, and 61 AD patients (median follow-up 3.5 years, range 0.6–7.8). We tested associations between baseline CSF α-synuclein and visual hallucinations and (longitudinal) cognition. Models were tested with and without co-varying for CSF total tau (T-tau), which is elevated in AD patients, and believed to reflect neurodegeneration. Results Hallucinations were reported in 20% of AD patients, 13% of MCI patients, and 8% of NC. In AD, low CSF α-synuclein was associated with hallucinations. When adjusting for CSF T-tau, low CSF α-synuclein was associated with accelerated decline of executive function (NC, MCI, and AD), memory (MCI and AD), and language (MCI). Conclusion The associations of low CSF α-synuclein with hallucinations and poor executive function, which are hallmarks of DLB, indirectly suggest that this biomarker may reflect underlying synuclein pathology. The associations with memory and language in MCI and AD suggests either that reduced CSF α-synuclein also partly reflects global impaired neuronal/synaptic function, or that non-specific overall cognitive deterioration is accelerated in the presence of synuclein related pathology. The findings will require autopsy verification.

Purpose of Review Posttraumatic stress disorder (PTSD) is associated with increased risk for dementia, yet mechanisms are poorly understood. Recent Findings Recent literature suggests several potential mechanisms by which sleep impairments might contribute to the increased risk of dementia observed in PTSD. First, molecular, animal, and imaging studies indicate that sleep problems lead to cellular damage in brain structures crucial to learning and memory. Second, recent studies have shown that lack of sleep might precipitate the accumulation of harmful amyloid proteins. Finally, sleep and PTSD are associated with elevated inflammation, which, in turn, is associated with dementia, possibly via cytokine-mediated neural toxicity and reduced neurogenesis. Summary A better understanding of these mechanisms may yield novel treatment approaches to reduce neurodegeneration in PTSD. The authors emphasize the importance of including sleep data in studies of PTSD and cognition and identify next steps.

Posttraumatic stress disorder (PTSD) is associated with smaller volumes of the hippocampus, as has been demonstrated by meta-analyses. Proposed mechanistic relationships are reviewed briefly, including the hypothesis that sleep disturbances mediate the effects of PTSD on hippocampal volume. Evidence for this includes findings that insomnia and restricted sleep are associated with changes in hippocampal cell regulation and impairments in cognition. We present results of a new study of 187 subjects in whom neither PTSD nor poor sleep was associated with lower hippocampal volume. We outline a broad research agenda centered on the hypothesis that sleep changes mediate the relationship between PTSD and hippocampal volume.

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