[1-11C]-Butanol Positron Emission Tomography reveals an impaired brain to nasal turbinates pathway in aging amyloid positive subjects.

BACKGROUND: Reduced clearance of cerebrospinal fluid (CSF) has been suggested as a pathological feature of Alzheimer's disease (AD). With extensive documentation in non-human mammals and contradictory human neuroimaging data it remains unknown whether the nasal mucosa is a CSF drainage site in humans. Here, we used dynamic PET with [1-11C]-Butanol, a highly permeable radiotracer with no appreciable brain binding, to test the hypothesis that tracer drainage from the nasal pathway reflects CSF drainage from brain. As a test of the hypothesis, we examined whether brain and nasal fluid drainage times were correlated and affected by brain amyloid. METHODS: 24 cognitively normal subjects (≥ 65 years) were dynamically PET imaged for 60 min. using [1-11C]-Butanol. Imaging with either [11C]-PiB or [18F]-FBB identified 8 amyloid PET positive (Aß+) and 16 Aß- subjects. MRI-determined regions of interest (ROI) included: the carotid artery, the lateral orbitofrontal (LOF) brain, the cribriform plate, and an All-turbinate region comprised of the superior, middle, and inferior turbinates. The bilateral temporalis muscle and jugular veins served as control regions. Regional time-activity were used to model tracer influx, egress, and AUC. RESULTS: LOF and All-turbinate 60 min AUC were positively associated, thus suggesting a connection between the brain and the nose. Further, the Aß+ subgroup demonstrated impaired tracer kinetics, marked by reduced tracer influx and slower egress. CONCLUSION: The data show that tracer kinetics for brain and nasal turbinates are related to each other and both reflect the amyloid status of the brain. As such, these data add to evidence that the nasal pathway is a potential CSF drainage site in humans. These data warrant further investigation of brain and nasal contributions to protein clearance in neurodegenerative disease.

Longitudinal Sleep Patterns and Cognitive Impairment in Older Adults.

Importance: Sleep disturbances and clinical sleep disorders are associated with all-cause dementia and neurodegenerative conditions, but it remains unclear how longitudinal changes in sleep impact the incidence of cognitive impairment. Objective: To evaluate the association of longitudinal sleep patterns with age-related changes in cognitive function in healthy older adults. Design, Setting, and Participants: This cross-sectional study is a retrospective longitudinal analyses of the Seattle Longitudinal Study (SLS), which evaluated self-reported sleep duration (1993-2012) and cognitive performance (1997-2020) in older adults. Participants within the SLS were enrolled as part of a community-based cohort from the Group Health Cooperative of Puget Sound and Health Maintenance Organization of Washington between 1956 and 2020. Data analysis was performed from September 2020 to May 2023. Main Outcomes and Measures: The main outcome for this study was cognitive impairment, as defined by subthreshold performance on both the Mini-Mental State Examination and the Mattis Dementia Rating Scale. Sleep duration was defined by self-report of median nightly sleep duration over the last week and was assessed longitudinally over multiple time points. Median sleep duration, sleep phenotype (short sleep, median ≤7 hours; medium sleep, median = 7 hour; long sleep, median ≥7 hours), change in sleep duration (slope), and variability in sleep duration (SD of median sleep duration, or sleep variability) were evaluated. Results: Of the participants enrolled in SLS, only 1104 participants who were administered both the Health Behavior Questionnaire and the neuropsychologic battery were included for analysis in this study. A total of 826 individuals (mean [SD] age, 76.3 [11.8] years; 468 women [56.7%]; 217 apolipoprotein E ε4 allele carriers [26.3%]) had complete demographic information and were included in the study. Analysis using a Cox proportional hazard regression model (concordance, 0.76) showed that status as a short sleeper (hazard ratio, 3.67; 95% CI, 1.59-8.50) and higher sleep variability (hazard ratio, 3.06; 95% CI, 1.14-5.49) were significantly associated with the incidence of cognitive impairment. Conclusions and Relevance: In this community-based longitudinal study of the association between sleep patterns and cognitive performance, the short sleep phenotype was significantly associated with impaired cognitive performance. Furthermore, high sleep variability in longitudinal sleep duration was significantly associated with the incidence of cognitive impairment, highlighting the possibility that instability in sleep duration over long periods of time may impact cognitive decline in older adults.

Instability in longitudinal sleep duration predicts cognitive impairment in aged participants of the Seattle Longitudinal Study.

Importance: Sleep disturbances and clinical sleep disorders are associated with all-cause dementia and neurodegenerative conditions. It remains unclear how longitudinal changes in sleep impact the incidence of cognitive impairment. Objective: To evaluate how longitudinal sleep patterns contribute to age-related changes in cognitive function in healthy adults. Design Setting Participants: This study utilizes retrospective longitudinal analyses of a community-based study within Seattle, evaluating self-reported sleep (1993-2012) and cognitive performance (1997-2020) in aged adults. Main Outcomes and Measures: The main outcome is cognitive impairment as defined by sub-threshold performance on 2 of 4 neuropsychological batteries: Mini-Mental State Examination (MMSE), Mattis Dementia Rating Scale, Trail Making Test, and Wechsler Adult Intelligent Scale (Revised). Sleep duration was defined through self-report of 'average nightly sleep duration over the last week' and assessed longitudinally. Median sleep duration, change in sleep duration (slope), variability in sleep duration (standard deviation, Sleep Variability), and sleep phenotype ("Short Sleep" median ≤7hrs.; "Medium Sleep" median = 7hrs; "Long Sleep" median ≥7hrs.). Results: A total of 822 individuals (mean age of 76.2 years [11.8]; 466 women [56.7%]; 216 APOE allele positive [26.3%]) were included in the study. Analysis using a Cox Proportional Hazard Regression model (concordance 0.70) showed that increased Sleep Variability (95% CI [1.27,3.86]) was significantly associated with the incidence of cognitive impairment. Further analysis using linear regression prediction analysis (R2=0.201, F (10, 168)=6.010, p=2.67E-07) showed that high Sleep Variability (ß=0.3491; p=0.048) was a significant predictor of cognitive impairment over a 10-year period. Conclusions and Relevance: High variability in longitudinal sleep duration was significantly associated with the incidence of cognitive impairment and predictive of decline in cognitive performance ten years later. These data highlight that instability in longitudinal sleep duration may contribute to age-related cognitive decline.

The effect of aquaporin-4 mis-localization on Aß deposition in mice.

The reduced clearance of amyloid-ß (Aß) is thought to contribute to the development of the pathology associated with Alzheimer's disease (AD), which is characterized by the deposition of Aß plaques. Previous studies have shown that Aß is cleared via the glymphatic system, a brain-wide network of perivascular pathways that supports the exchange between cerebrospinal fluid and interstitial fluid within the brain. Such exchange is dependent upon the water channel aquaporin-4 (AQP4), localized at astrocytic endfeet. While prior studies have shown that both the loss and mislocalization of AQP4 slow Aß clearance and promote Aß plaque formation, the relative impact of the loss or mislocalization of AQP4 on Aß deposition has never been directly compared. In this study, we evaluated how the deposition of Aß plaques within the 5XFAD mouse line is impacted by either Aqp4 gene deletion or the loss of AQP4 localization in the α-syntrophin (Snta1) knockout mouse. We observed that both the absence (Aqp4 KO) and mislocalization (Snta1 KO) of AQP4 significantly increases the parenchymal Aß plaque and microvascular Aß deposition across the brain, when compared with 5XFAD littermate controls. Further, the mislocalization of AQP4 had a more pronounced impact on Aß plaque deposition than did global Aqp4 gene deletion, perhaps pointing to a key role that mislocalization of perivascular AQP4 plays in AD pathogenesis.

Dynamic infrared imaging of cerebrospinal fluid tracer influx into the brain.

Significance: The glymphatic system has been described recently as a series of perivascular channels that facilitate fluid exchange and solute clearance in the brain. Glymphatic dysfunction has been implicated in numerous pathological conditions, including Alzheimer's disease, traumatic brain injury, and stroke. Existing methods for assessing glymphatic function have been challenging: dynamic methods, such as two-photon microscopy and contrast-enhanced magnetic resonance imaging require expensive instrumentation and specific technical skills; slice-based fluorescent imaging is more readily implemented but lacks temporal resolution. Aim: To develop a straightforward and adaptable dynamic imaging approach for assessing glymphatic function in vivo in mice. Approach: Using a widely available small animal infrared (IR) imaging system (LICOR Pearl), visualization of IR cerebrospinal fluid tracer distribution over the cortical surface enables time-resolved measurement of the dynamics of glymphatic exchange. Using co-injection of IR and conventional fixable fluorescent tracers, dynamic imaging can be paired with whole-slice fluorescence imaging, permitting the quantification of glymphatic function throughout the brain as well as subsequent histological assessment. Results: These techniques were validated against one another, comparing differences between animals anesthetized with ketamine/xylazine and isoflurane. Conclusions: This technique permits sensitive dynamic imaging of glymphatic function, with the concurrent visualization of resolution of deeper structures.