White matter hyperintensities and the surrounding normal appearing white matter are associated with water channel disruption in the oldest old.

INTRODUCTION: Age-related magnetic resonance imaging (MRI) T2 white matter hyperintensities (WMHs) are common and associated with neurological decline. We investigated the histopathological underpinnings of MRI WMH and surrounding normal appearing white matter (NAWM), with a focus on astroglial phenotypes. METHODS: Brain samples from 51 oldest old Oregon Alzheimer's Disease Research Center participants who came to autopsy underwent post mortem (PM) 7 tesla MRI with targeted histopathological sampling of WMHs and NAWM. Stained slides were digitized and quantified. Mixed-effects models determined differences in molecular characteristics between WMHs and the NAWM and across NAWM. RESULTS: PM MRI-targeted WMHs are characterized by demyelination, microglial activation, and prominent astrocytic alterations, including disrupted aquaporin (AQP) expression. Similar changes occur within the surrounding NAWM in a pattern of decreasing severity with increased distance from WMHs. DISCUSSION: Decreased AQP expression within WMH and proximal NAWM suggest an overwhelmed system wherein water homeostasis is no longer maintained, contributing to WM damage in older individuals. HIGHLIGHTS: Post mortem magnetic resonance imaging (MRI) was used to characterize the pathology of white matter hyperintensities (WMHs) and surrounding normal appearing white matter (NAWM). Stained immunohistochemical (IHC) slides from targeted WMH and NAWM samples were digitized and quantified. WMHs and NAWM were associated with inflammation, demyelination, and gliosis. WMHs and NAWM astrocytic changes included decreased AQP1 and AQP4 expression. Abnormal NAWM pathology diminished in severity with increasing distance from WMH.

Venous Collagenosis as Pathogenesis of White Matter Hyperintensity.

OBJECTIVE: Periventricular white matter hyperintensities (pvWMHs) are commonly observed on MRI in older individuals and are associated with cognitive and motor decline. The etiology of pvWMH remains unknown. Venous collagenosis has been implicated, which may also interfere with perivascular fluid flow leading to dilation of perivascular spaces (PVS). Here, we examine relationships between in vivo pvWMH volume and ex vivo morphological quantification of collagenosis and the PVS in veins and arteries. METHODS: Brain tissue from 25 Oregon Alzheimer's Disease Research Center subjects was selected to cover the full range of WMH burden. Tissue from white matter abutting the ventricle was stained with Masson's trichrome and smooth muscle actin. An automated hue based algorithm identified and segmented vessel into collagenized vessel walls, lumen, and PVS. Multiple linear regressions with pvWMH volume as the dependent variable and either collagen thickness or PVS width were performed with covariates of vessel diameter, age at death, sex, and interval between MRI and death. RESULTS: PVS width and collagen thickness were significantly correlated in both arteries (r = 0.21, p = 0.001) and veins (r = 0.23, p = 0.001). Increased venous collagen (p = 0.017) was a significant predictor of higher pvWMH burden while arterial collagen was not (p = 0.128). Neither PVS width in arteries (p = 0.937) nor veins (p = 0.133) predicted pvWMH burden. INTERPRETATION: These findings are consistent with a model in which venous collagenosis mediates the relationship between vascular risk factors and pvWMH. This study confirms the importance of changes to the venous system in contributing to MRI white matter lesions commonly observed with advanced age. ANN NEUROL 2022;92:992-1000.

Remote Spectral Light Sensing in the Home Environment: Further Development of the TWLITE Study Concept.

Aging is a significant contributor to changes in sleep patterns, which has compounding consequences on cognitive health. A modifiable factor contributing to poor sleep is inadequate and/or mistimed light exposure. However, methods to reliably and continuously collect light levels long-term in the home, a necessity for informing clinical guidance, are not well established. We explored the feasibility and acceptability of remote deployment and the fidelity of long-term data collection for both light levels and sleep within participants' homes. The original TWLITE study utilized a whole-home tunable lighting system, while the current project is an observational study of the light environment already existing in the home. This was a longitudinal, observational, prospective pilot study involving light sensors remotely deployed in the homes of healthy adults (n = 16, mean age: 71.7 years, standard deviation: 5.0 years) who were co-enrolled in the existing Collaborative Aging (in Place) Research Using Technology (CART) sub-study within the Oregon Center for Aging and Technology (ORCATECH). For 12 weeks, light levels were recorded via light sensors (ActiWatch Spectrum), nightly sleep metrics were recorded via mattress-based sensors, and daily activity was recorded via wrist-based actigraphy. Feasibility and acceptability outcomes indicated that participants found the equipment easy to use and unobtrusive. This proof-of-concept, feasibility/acceptability study provides evidence that light sensors can be remotely deployed to assess relationships between light exposure and sleep among older adults, paving the way for measurement of light levels in future studies examining lighting interventions to improve sleep.

Mood and activity changes during the COVID-19 pandemic in rural and urban Veterans and their cohabitants.

OBJECTIVES: We aimed to examine the impact of COVID-19 pandemic-related stay-at-home orders on weekly reports of mood and activity before and during COVID-19 in a sample of older Veterans and their cohabitants. METHODS: Urban and rural Veterans and their cohabitants living in the Pacific Northwest ≥62 years old were enrolled as part of the Collaborative Aging Research Using Technology initiative (n = 100, age = 71.2 ± 6.5, 41% women). Participants reported frequency of social activities (e.g., travel away), physical illness, and mood (blue mood and loneliness) via weekly online health forms. RESULTS: A total of 2,441 weekly online health forms (OHFs) were collected from 100 participants. During the COVID-19 pandemic, blue mood (OR = 4.4, p < .0001) and loneliness (OR = 7.2, p < .0001) were significantly higher than before the pandemic, and travel away from home was significantly lower (OR = 0.5, p < .0001). Prevalence of blue mood and loneliness were not associated with rurality. CONCLUSIONS: The current study established that blue mood and loneliness were significantly more prevalent in older Veterans following COVID-19 stay-at-home orders regardless of rurality. CLINICAL IMPLICATIONS: The COVID-19 pandemic associated health precautions, while necessary to curb acute health risks, have created a unique situation that places vulnerable populations at increased risk of low mood.

Autoidentification of perivascular spaces in white matter using clinical field strength T1 and FLAIR MR imaging.

Recent interest in enlarged perivascular spaces (ePVS) in the brain, which can be visualized on MRI and appear isointense to cerebrospinal fluid on all sequence weightings, has resulted in the necessity of reliable algorithms for automated segmentation to allow for whole brain assessment of ePVS burden. However, several publicly available datasets do not contain sequences required for recently published algorithms. This prospective study presents a method for identification of enlarged perivascular spaces (ePVS) in white matter using 3T T1 and FLAIR MR imaging (MAPS-T1), making the algorithm accessible to groups with valuable sets of limited data. The approach was applied identically to two datasets: 1) a repeated measurement in a dementia-free aged human population (N = 14), and 2) an aged sample of multisite ADNI datasets (N = 30). ePVS segmentation was accomplished by a stepwise local homogeneity search of white matter-masked T1-weighted data, constrained by FLAIR hyperintensity, and further constrained by width, volume, and linearity measurements. Pearson's r was employed for statistical testing between visual (gold standard) assessment and repeated measures in cohort one. Visual ePVS counts were significantly correlated with MAPS-T1 (r = .72, P < .0001). Correlations between repeated measurements in cohort one were significant for both visual and automated methods in the single visually-rated slice (MAPS-T1: r = .87, P < .0001, visual: (r = .86, P < .0001) and for whole brain assessment (MAPS-T1: r = .77, P = .001). Results from each cohort were manually inspected and found to have positive predictive values of 77.5% and 87.5%, respectively. The approach described in this report is an important tool for detailed assessment of ePVS burden in white matter on routinely acquired MRI sequences.

MR Imaging-based Multimodal Autoidentification of Perivascular Spaces (mMAPS): Automated Morphologic Segmentation of Enlarged Perivascular Spaces at Clinical Field Strength.

Purpose To describe a fully automated segmentation method that yields object-based morphologic estimates of enlarged perivascular spaces (ePVSs) in clinical-field-strength (3.0-T) magnetic resonance (MR) imaging data. Materials and Methods In this HIPAA-compliant study, MR imaging data were obtained with a 3.0-T MR imager in research participants without dementia (mean age, 85.3 years; range, 70.4-101.2 years) who had given written informed consent. This method is built on (a) relative normalized white matter, ventricular and cortical signal intensities within T1-weighted, fluid-attenuated inversion recovery, T2-weighted, and proton density data and (b) morphologic (width, volume, linearity) characterization of each resultant cluster. Visual rating was performed by three raters, including one neuroradiologist, after established single-section guidelines. Correlations between visual counts and automated counts, as well session-to-session correlation of counts within each participant, were assessed with the Pearson correlation coefficient r. Results There was a significant correlation between counts by visual raters and automated detection of ePVSs in the same section (r = 0.65, P < .001; r = 0.69, P < .001; and r = 0.54, P < .01 for raters 1, 2, and 3, respectively). With regard to visual ratings and whole-brain count consistency, average visual rating scores were highly correlated with automated detection of total burden volume (r = 0.58, P < .01) and total ePVS number (r = 0.76, P < .01). Morphology of clusters across 28 data sets was consistent with published radiographic estimates of ePVS; mean width of clusters segmented was 3.12 mm (range, 1.7-13.5 mm). Conclusion This MR imaging-based method for multimodal autoidentification of perivascular spaces yields individual whole-brain morphologic characterization of ePVS in clinical MR imaging data and is an important tool in the detailed assessment of these features. © RSNA, 2017 Online supplemental material is available for this article.

Risk of incident clinical diagnosis of Alzheimer's disease-type dementia attributable to pathology-confirmed vascular disease.

INTRODUCTION: The presence of cerebrovascular pathology may increase the risk of clinical diagnosis of Alzheimer's disease (AD). METHODS: We examined excess risk of incident clinical diagnosis of AD (probable and possible AD) posed by the presence of lacunes and large infarcts beyond AD pathology using data from the Statistical Modeling of Aging and Risk of Transition study, a consortium of longitudinal cohort studies with more than 2000 autopsies. We created six mutually exclusive pathology patterns combining three levels of AD pathology (low, moderate, or high AD pathology) and two levels of vascular pathology (without lacunes and large infarcts or with lacunes and/or large infarcts). RESULTS: The coexistence of lacunes and large infarcts results in higher likelihood of clinical diagnosis of AD only when AD pathology burden is low. DISCUSSION: Our results reinforce the diagnostic importance of AD pathology in clinical AD. Further harmonization of assessment approaches for vascular pathologies is required.

Surgery is associated with ventricular enlargement as well as cognitive and functional decline.

INTRODUCTION: In preclinical studies, surgery/anesthesia contribute to cognitive decline and enhance neuropathologic changes underlying Alzheimer's disease (AD). Nevertheless, the link between surgery, anesthesia, apolipoprotein E ε4 (APOE ε4), and AD remains unclear. METHODS: We performed a retrospective cohort analysis of two prospective longitudinal aging studies. Mixed-effects statistical models were used to assess the relationship between surgical/anesthetic exposure, the APOE genotype, and rate of change in measures of cognition, function, and brain volumes. RESULTS: The surgical group (n = 182) experienced a more rapid rate of deterioration compared with the nonsurgical group (n = 345) in several cognitive, functional, and brain magnetic resonance imaging measures. Furthermore, there was a significant synergistic effect of anesthesia/surgery exposure and presence of the APOE ε4 allele in the decline of multiple cognitive and functional measures. DISCUSSION: These data provide insight into the role of surgical exposure as a risk factor for cognitive and functional decline in older adults.

At the interface of sensory and motor dysfunctions and Alzheimer's disease.

Recent evidence indicates that sensory and motor changes may precede the cognitive symptoms of Alzheimer's disease (AD) by several years and may signify increased risk of developing AD. Traditionally, sensory and motor dysfunctions in aging and AD have been studied separately. To ascertain the evidence supporting the relationship between age-related changes in sensory and motor systems and the development of AD and to facilitate communication between several disciplines, the National Institute on Aging held an exploratory workshop titled "Sensory and Motor Dysfunctions in Aging and AD." The scientific sessions of the workshop focused on age-related and neuropathologic changes in the olfactory, visual, auditory, and motor systems, followed by extensive discussion and hypothesis generation related to the possible links among sensory, cognitive, and motor domains in aging and AD. Based on the data presented and discussed at this workshop, it is clear that sensory and motor regions of the central nervous system are affected by AD pathology and that interventions targeting amelioration of sensory-motor deficits in AD may enhance patient function as AD progresses.

The EADC-ADNI Harmonized Protocol for manual hippocampal segmentation on magnetic resonance: evidence of validity.

BACKGROUND: An international Delphi panel has defined a harmonized protocol (HarP) for the manual segmentation of the hippocampus on MR. The aim of this study is to study the concurrent validity of the HarP toward local protocols, and its major sources of variance. METHODS: Fourteen tracers segmented 10 Alzheimer's Disease Neuroimaging Initiative (ADNI) cases scanned at 1.5 T and 3T following local protocols, qualified for segmentation based on the HarP through a standard web-platform and resegmented following the HarP. The five most accurate tracers followed the HarP to segment 15 ADNI cases acquired at three time points on both 1.5 T and 3T. RESULTS: The agreement among tracers was relatively low with the local protocols (absolute left/right ICC 0.44/0.43) and much higher with the HarP (absolute left/right ICC 0.88/0.89). On the larger set of 15 cases, the HarP agreement within (left/right ICC range: 0.94/0.95 to 0.99/0.99) and among tracers (left/right ICC range: 0.89/0.90) was very high. The volume variance due to different tracers was 0.9% of the total, comparing favorably to variance due to scanner manufacturer (1.2), atrophy rates (3.5), hemispheric asymmetry (3.7), field strength (4.4), and significantly smaller than the variance due to atrophy (33.5%, P < .001), and physiological variability (49.2%, P < .001). CONCLUSIONS: The HarP has high measurement stability compared with local segmentation protocols, and good reproducibility within and among human tracers. Hippocampi segmented with the HarP can be used as a reference for the qualification of human tracers and automated segmentation algorithms.

Role of soluble epoxide hydrolase in age-related vascular cognitive decline.

P450 eicosanoids are important regulators of the cerebral microcirculation, but their role in cerebral small vessel disease is unclear. We tested the hypothesis that vascular cognitive impairment (VCI) is linked to reduced cerebral microvascular eicosanoid signaling. We analyzed human brain tissue from individuals formerly enrolled in the Oregon Brain Aging Study, who had a history of cognitive impairment histopathological evidence of microvascular disease. VCI subjects had significantly higher lesion burden both on premortem MRI and postmortem histopathology compared to age- and sex-matched controls. Mass spectrometry-based eicosanoid analysis revealed that 14,15-dihydroxyeicosatrienoic acid (DHET) was elevated in cortical brain tissue from VCI subjects. Immunoreactivity of soluble epoxide hydrolase (sEH), the enzyme responsible for 14,15-DHET formation, was localized to cerebral microvascular endothelium, and was enhanced in microvessels of affected tissue. Finally, we evaluated the genotype frequency of two functional single nucleotide polymorphisms of sEH gene EPHX2 in VCI and control groups. Our findings support a role for sEH and a potential benefit from sEH inhibitors in age-related VCI.

Biomarker progressions explain higher variability in stage-specific cognitive decline than baseline values in Alzheimer disease.

BACKGROUND: It is unknown which commonly used Alzheimer disease (AD) biomarker values-baseline or progression-best predict longitudinal cognitive decline. METHODS: 526 subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI). ADNI composite memory and executive scores were the primary outcomes. Individual-specific slope of the longitudinal trajectory of each biomarker was first estimated. These estimates and observed baseline biomarker values were used as predictors of cognitive declines. Variability in cognitive declines explained by baseline biomarker values was compared with variability explained by biomarker progression values. RESULTS: About 40% of variability in memory and executive function declines was explained by ventricular volume progression among mild cognitive impairment patients. A total of 84% of memory and 65% of executive function declines were explained by fluorodeoxyglucose positron emission tomography (FDG-PET) score progression and ventricular volume progression, respectively, among AD patients. CONCLUSIONS: For most biomarkers, biomarker progressions explained higher variability in cognitive decline than biomarker baseline values. This has important implications for clinical trials targeted to modify AD biomarkers.

Internet-Based Conversational Engagement Randomized Controlled Clinical Trial (I-CONECT) Among Socially Isolated Adults 75+ Years Old With Normal Cognition or Mild Cognitive Impairment: Topline Results.

BACKGROUND AND OBJECTIVES: Social isolation is a risk factor for cognitive decline and dementia. We conducted a randomized controlled clinical trial (RCT) of enhanced social interactions, hypothesizing that conversational interactions can stimulate brain functions among socially isolated older adults without dementia. We report topline results of this multisite RCT (Internet-based conversational engagement clinical trial [I-CONECT]; NCT02871921). RESEARCH DESIGN AND METHODS: The experimental group received cognitively stimulating semistructured conversations with trained interviewers via internet/webcam 4 times per week for 6 months (induction) and twice per week for an additional 6 months (maintenance). The experimental and control groups both received weekly 10 minutes telephone check-ins. Protocol modifications were required due to the coronavirus disease 2019 pandemic. RESULTS: A total of 186 participants were randomized. After the induction period, the experimental group had higher global cognitive test scores (Montreal Cognitive Assessment [primary outcome]; 1.75 points [p = .03]) compared with the control group. After induction, experimental group participants with normal cognition had higher language-based executive function (semantic fluency test [secondary outcome]; 2.56 points [p = .03]). At the end of the maintenance period, the experimental group of mild cognitive impairment subjects had higher encoding function (Craft Story immediate recall test [secondary outcome]; 2.19 points [p = .04]). Measure of emotional well-being improved in both control and experimental groups. Resting-state functional magnetic resonance imaging showed that the experimental group had increased connectivity within the dorsal attention network relative to the control group (p = .02), but the sample size was limited. DISCUSSION AND IMPLICATIONS: Providing frequent stimulating conversational interactions via the internet could be an effective home-based dementia risk-reduction strategy against social isolation and cognitive decline. CLINICAL TRIALS REGISTRATION NUMBER: NCT02871921.

Enlarged perivascular spaces are associated with white matter injury, cognition and inflammation in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

Enlarged perivascular spaces have been previously reported in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, but their significance and pathophysiology remains unclear. We investigated associations of white matter enlarged perivascular spaces with classical imaging measures, cognitive measures and plasma proteins to better understand what enlarged perivascular spaces represent in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy and whether radiographic measures of enlarged perivascular spaces would be of value in future therapeutic discovery studies for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Twenty-four individuals with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy and 24 age- and sex-matched controls were included. Disease status was determined based on the presence of NOTCH3 mutation. Brain imaging measures of white matter hyperintensity, brain parenchymal fraction, white matter enlarged perivascular space volumes, clinical and cognitive measures as well as plasma proteomics were used in models. White matter enlarged perivascular space volumes were calculated via a novel, semiautomated pipeline, and levels of 7363 proteins were quantified in plasma using the SomaScan assay. The relationship of enlarged perivascular spaces with global burden of white matter hyperintensity, brain atrophy, functional status, neurocognitive measures and plasma proteins was modelled with linear regression models. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy and control groups did not exhibit differences in mean enlarged perivascular space volumes. However, increased enlarged perivascular space volumes in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy were associated with increased white matter hyperintensity volume (ß = 0.57, P = 0.05), Clinical Dementia Rating Sum-of-Boxes score (ß = 0.49, P = 0.04) and marginally with decreased brain parenchymal fraction (ß = -0.03, P = 0.10). In interaction term models, the interaction term between cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy disease status and enlarged perivascular space volume was associated with increased white matter hyperintensity volume (ß = 0.57, P = 0.02), Clinical Dementia Rating Sum-of-Boxes score (ß = 0.52, P = 0.02), Mini-Mental State Examination score (ß = -1.49, P = 0.03) and marginally with decreased brain parenchymal fraction (ß = -0.03, P = 0.07). Proteins positively associated with enlarged perivascular space volumes were found to be related to leukocyte migration and inflammation, while negatively associated proteins were related to lipid metabolism. Two central hub proteins were identified in protein networks associated with enlarged perivascular space volumes: CXC motif chemokine ligand 8/interleukin-8 and C-C motif chemokine ligand 2/monocyte chemoattractant protein 1. The levels of CXC motif chemokine ligand 8/interleukin-8 were also associated with increased white matter hyperintensity volume (ß = 42.86, P = 0.03), and levels of C-C motif chemokine ligand 2/monocyte chemoattractant protein 1 were further associated with decreased brain parenchymal fraction (ß = -0.0007, P < 0.01) and Mini-Mental State Examination score (ß = -0.02, P < 0.01) and increased Trail Making Test B completion time (ß = 0.76, P < 0.01). No proteins were associated with all three studied imaging measures of pathology (brain parenchymal fraction, enlarged perivascular spaces, white matter hyperintensity). Based on associations uncovered between enlarged perivascular space volumes and cognitive functions, imaging and plasma proteins, we conclude that white matter enlarged perivascular space volumes may capture pathologies contributing to chronic brain dysfunction and degeneration in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

Dynamic changes in perivascular space morphology predict signs of spaceflight-associated neuro-ocular syndrome in bed rest.

During long-duration spaceflight, astronauts experience headward fluid shifts and expansion of the cerebral perivascular spaces (PVS). A major limitation to our understanding of the changes in brain structure and physiology induced by spaceflight stems from the logistical difficulties of studying astronauts. The current study aimed to determine whether PVS changes also occur on Earth with the spaceflight analog head-down tilt bed rest (HDBR). We examined how the number and morphology of magnetic resonance imaging-visible PVS (MV-PVS) are affected by HDBR with and without elevated carbon dioxide (CO2). These environments mimic the headward fluid shifts, body unloading, and elevated CO2 observed aboard the International Space Station. Additionally, we sought to understand how changes in MV-PVS are associated with signs of Spaceflight Associated Neuro-ocular Syndrome (SANS), ocular structural alterations that can occur with spaceflight. Participants were separated into two bed rest campaigns: HDBR (60 days) and HDBR + CO2 (30 days with elevated ambient CO2). Both groups completed multiple magnetic resonance image acquisitions before, during, and post-bed rest. We found that at the group level, neither spaceflight analog affected MV-PVS quantity or morphology. However, when taking into account SANS status, persons exhibiting signs of SANS showed little or no MV-PVS changes, whereas their No-SANS counterparts showed MV-PVS morphological changes during the HDBR + CO2 campaign. These findings highlight spaceflight analogs as models for inducing changes in MV-PVS and implicate MV-PVS dynamic compliance as a mechanism underlying SANS. These findings may lead to countermeasures to mitigate health risks associated with human spaceflight.

Role of white matter hyperintensity in effects of apolipoprotein E on cognitive injury.

Magnetic Resonance Imaging (MRI) T2-weighted white matter hyperintensity (WMH) is a marker of small vessel cerebrovascular pathology and is of ischemic origin. The prevalence and severity of WMH is associated with cardiovascular risk factors, aging, and cognitive injury in mild cognitive impairment (MCI), vascular dementia, and Alzheimer's disease (AD). WMH especially affects executive function, with additional effects on memory and global cognition. Apolipoprotein E (apoE) plays a role in cholesterol metabolism and neuronal repair after injury. Human and animal studies support a role for apoE in maintaining white matter integrity. In humans, there are three major human apoE isoforms, E2, E3, and E4. Human apoE isoforms differ in risk to develop AD and in association with WMH. In this Mini Review, we propose an increased focus on the role of WMH in cognitive health and cognitive injury and the likely role of apoE and apoE isoform in modulating these effects. We hypothesize that apoE and apoE isoforms play a role in modulating WMH via apoE isoform-dependent effects on oxylipins and 7-ketocholesterol, as well as amyloid related vascular injury, as seen in cerebral amyloid angiopathy.

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.

Associations of Enlarged Perivascular Spaces With Brain Lesions, Brain Age, and Clinical Outcomes in Chronic Traumatic Brain Injury.

BACKGROUND AND OBJECTIVES: Enlarged perivascular spaces (ePVS) have been identified as a key signature of glymphatic system dysfunction in neurologic conditions. The incidence and clinical implications of ePVS after traumatic brain injury (TBI) are not yet understood. We investigated whether individuals with chronic moderate-to-severe TBI had an increased burden of ePVS and whether ePVS burden is modulated by the presence of focal lesions, older brain age, and poorer sleep quality. We examined whether an increased burden of ePVS was associated with poorer cognitive and emotional outcomes. METHODS: Using a cross-sectional design, participants with a single moderate-to-severe chronic TBI (sustained ≥10 years ago) were recruited from an inpatient rehabilitation program. Control participants were recruited from the community. Participants underwent 3T brain MRI, neuropsychological assessment, and clinical evaluations. ePVS burden in white matter was quantified using automated segmentation. The relationship between the number of ePVS, group membership, focal lesions, brain age, current sleep quality, and outcome was modeled using negative binomial and linear regressions. RESULTS: This study included 100 participants with TBI (70% male; mean age = 56.8 years) and 75 control participants (54.3% male; mean age = 59.8 years). The TBI group had a significantly greater burden of ePVS (prevalence ratio rate [PRR] = 1.29, p = 0.013, 95% CI 1.05-1.57). The presence of bilateral lesions was associated with greater ePVS burden (PRR = 1.41, p = 0.021, 95% CI 1.05-1.90). There was no association between ePVS burden, sleep quality (PRR = 1.01, p = 0.491, 95% CI 0.98-1.048), and sleep duration (PRR = 1.03, p = 0.556, 95% CI 0.92-1.16). ePVS was associated with verbal memory (ß = -0.42, p = 0.006, 95% CI -0.72 to -0.12), but not with other cognitive domains. The burden of ePVS was not associated with emotional distress (ß = -0.70, p = 0.461, 95% CI -2.57 to 1.17) or brain age (PRR = 1.00, p = 0.665, 95% CI 0.99-1.02). DISCUSSION: TBI is associated with a greater burden of ePVS, especially when there have been bilateral brain lesions. ePVS was associated with reduced verbal memory performance. ePVS may indicate ongoing impairments in glymphatic system function in the chronic postinjury period.

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.

Differences in Life Space Activity Patterns Between Older Adults With Mild Cognitive Impairment Living Alone or as a Couple: Cohort Study Using Passive Activity Sensing.

BACKGROUND: Measuring function with passive in-home sensors has the advantages of real-world, objective, continuous, and unobtrusive measurement. However, previous studies have focused on 1-person homes only, which limits their generalizability. OBJECTIVE: This study aimed to compare the life space activity patterns of participants living alone with those of participants living as a couple and to compare people with mild cognitive impairment (MCI) with cognitively normal participants in both 1- and 2-person homes. METHODS: Passive infrared motion sensors and door contact sensors were installed in 1- and 2-person homes with cognitively normal residents or residents with MCI. A home was classified as an MCI home if at least 1 person in the home had MCI. Time out of home (TOOH), independent life space activity (ILSA), and use of the living room, kitchen, bathroom, and bedroom were calculated. Data were analyzed using the following methods: (1) daily averages over 4 weeks, (2) hourly averages (time of day) over 4 weeks, or (3) longitudinal day-to-day changes. RESULTS: In total, 129 homes with people living alone (n=27, 20.9%, MCI and n=102, 79.1%, no-MCI homes) and 52 homes with people living as a couple (n=24, 46.2%, MCI and n=28, 53.8%, no-MCI homes) were included with a mean follow-up of 719 (SD 308) days. Using all 3 analysis methods, we found that 2-person homes showed a shorter TOOH, a longer ILSA, and shorter living room and kitchen use. In MCI homes, ILSA was higher in 2-person homes but lower in 1-person homes. The effects of MCI status on other outcomes were only found when using the hourly averages or longitudinal day-to-day changes over time, and they depended on the household type (alone vs residing as a couple). CONCLUSIONS: This study shows that in-home behavior is different when a participant is living alone compared to when they are living as a couple, meaning that the household type should be considered when studying in-home behavior. The effects of MCI status can be detected with in-home sensors, even in 2-person homes, but data should be analyzed on an hour-to-hour basis or longitudinally.