Cerebrovascular reactivity MRI as a biomarker for cerebral small vessel disease-related cognitive decline: Multi-site validation in the MarkVCID Consortium.

INTRODUCTION: Vascular contributions to cognitive impairment and dementia (VCID) represent a major factor in cognitive decline in older adults. The present study examined the relationship between cerebrovascular reactivity (CVR) measured by magnetic resonance imaging (MRI) and cognitive function in a multi-site study, using a predefined hypothesis. METHODS: We conducted the study in a total of three analysis sites and 263 subjects. Each site performed an identical CVR MRI procedure using 5% carbon dioxide inhalation. A global cognitive measure of Montreal Cognitive Assessment (MoCA) and an executive function measure of item response theory (IRT) score were used as outcomes. RESULTS: CVR and MoCA were positively associated, and this relationship was reproduced at all analysis sites. CVR was found to be positively associated with executive function. DISCUSSION: The predefined hypothesis on the association between CVR and a global cognitive score was validated in three independent analysis sites, providing support for CVR as a biomarker in VCID. HIGHLIGHTS: This study measured a novel functional index of small arteries referred to as cerebrovascular reactivity (CVR). CVR was positively associated with global cognition in older adults. This finding was observed in three independent cohorts at three sites. Our statistical analysis plan was predefined before beginning data collection.

MRI free water mediates the association between water exchange rate across the blood brain barrier and executive function among older adults.

Vascular risk factors contribute to cognitive aging, with one such risk factor being dysfunction of the blood brain barrier (BBB). Studies using non-invasive magnetic resonance imaging (MRI) techniques, such as diffusion prepared arterial spin labeling (DP-ASL), can estimate BBB function by measuring water exchange rate (kw). DP-ASL kw has been associated with cognition, but the directionality and strength of the relationship is still under investigation. An additional variable that measures water in extracellular space and impacts cognition, MRI free water (FW), may help explain prior findings. A total of 94 older adults without dementia (Mean age = 74.17 years, 59.6% female) underwent MRI (DP-ASL, diffusion weighted imaging (DWI)) and cognitive assessment. Mean kw was computed across the whole brain (WB), and mean white matter FW was computed across all white matter. The relationship between kw and three cognitive domains (executive function, processing speed, memory) was tested using multiple linear regression. FW was tested as a mediator of the kw-cognitive relationship using the PROCESS macro. A positive association was found between WB kw and executive function [F(4,85) = 7.81, p < .001, R2= 0.269; ß = .245, p = .014]. Further, this effect was qualified by subsequent results showing that FW was a mediator of the WB kw-executive function relationship (indirect effect results: standardized effect = .060, bootstrap confidence interval = .0006 to .1411). Results suggest that lower water exchange rate (kw) may contribute to greater total white matter (WM) FW which, in turn, may disrupt executive function. Taken together, proper fluid clearance at the BBB contributes to higher-order cognitive abilities.

Regional differences in the link between water exchange rate across the blood-brain barrier and cognitive performance in normal aging.

The blood-brain barrier (BBB) undergoes functional changes with aging which may contribute to cognitive decline. A novel, diffusion prepared arterial spin labeling-based MRI technique can measure the rate of water exchange across the BBB (kw) and may thus be sensitive to age-related alterations in water exchange at the BBB. However, studies investigating relationships between kw and cognition have reported different directions of association. Here, we begin to investigate the direction of associations between kw and cognition in different brain regions, and their possible underpinnings, by evaluating links between kw, cognitive performance, and MRI markers of cerebrovascular dysfunction and/or damage. Forty-seven healthy older adults (age range 61-84) underwent neuroimaging to obtain whole-brain measures of kw, cerebrovascular reactivity (CVR), and white matter hyperintensity (WMH) volumes. Additionally, participants completed uniform data set (Version 3) neuropsychological tests of executive function (EF) and episodic memory (MEM). Voxel-wise linear regressions were conducted to test associations between kw and cognitive performance, CVR, and WMH volumes. We found that kw in the frontoparietal brain regions was positively associated with cognitive performance but not with CVR or WMH volumes. Conversely, kw in the basal ganglia was negatively associated with cognitive performance and CVR and positively associated with regional, periventricular WMH volume. These regionally dependent associations may relate to different physiological underpinnings in the relationships between kw and cognition in neocortical versus subcortical brain regions in older adults.

Association of Baseline Cerebrovascular Reactivity and Longitudinal Development of Enlarged Perivascular Spaces in the Basal Ganglia.

BACKGROUND: Increasing evidence suggests that enlarged perivascular spaces (ePVS) are associated with cognitive dysfunction in aging. However, the pathogenesis of ePVS remains unknown. Here, we tested the possibility that baseline cerebrovascular dysfunction, as measured by a magnetic resonance imaging measure of cerebrovascular reactivity, contributes to the later development of ePVS. METHODS: Fifty cognitively unimpaired, older adults (31 women; age range, 60-84 years) underwent magnetic resonance imaging scanning at baseline and follow-up separated by ≈2.5 years. ePVS were counted in the basal ganglia, centrum semiovale, midbrain, and hippocampus. Cerebrovascular reactivity, an index of the vasodilatory capacity of cerebral small vessels, was assessed using carbon dioxide inhalation while acquiring blood oxygen level-dependent magnetic resonance images. RESULTS: Low baseline cerebrovascular reactivity values in the basal ganglia were associated with increased follow-up ePVS counts in the basal ganglia after controlling for age, sex, and baseline ePVS values (estimate [SE]=-3.18 [0.96]; P=0.002; [95% CI, -5.11 to -1.24]). This effect remained significant after accounting for self-reported risk factors of cerebral small vessel disease (estimate [SE]=-3.10 [1.00]; P=0.003; [CI, -5.11 to -1.09]) and neuroimaging markers of cerebral small vessel disease (estimate [SE]=-2.72 [0.99]; P=0.009; [CI, -4.71 to -0.73]). CONCLUSIONS: Our results demonstrate that low baseline cerebrovascular reactivity is a risk factor for later development of ePVS.

Plasma TDP-43 levels are associated with neuroimaging measures of brain structure in limbic regions.

Introduction: We evaluated the relationship between plasma levels of transactive response DNA binding protein of 43 kDa (TDP-43) and neuroimaging (magnetic resonance imaging [MRI]) measures of brain structure in aging. Methods: Plasma samples were collected from 72 non-demented older adults (age range 60-94 years) in the University of Kentucky Alzheimer's Disease Research Center cohort. Multivariate linear regression models were run with plasma TDP-43 level as the predictor variable and brain structure (volumetric or cortical thickness) measurements as the dependent variable. Covariates included age, sex, intracranial volume, and plasma markers of Alzheimer's disease neuropathological change (ADNC). Results: Negative associations were observed between plasma TDP-43 level and both the volume of the entorhinal cortex, and cortical thickness in the cingulate/parahippocampal gyrus, after controlling for ADNC plasma markers. Discussion: Plasma TDP-43 levels may be directly associated with structural MRI measures. Plasma TDP-43 assays may prove useful in clinical trial stratification. HIGHLIGHTS: Plasma transactive response DNA binding protein of 43 kDa (TDP-43) levels were associated with entorhinal cortex volume.Biomarkers of TDP-43 and Alzheimer's disease neuropathologic change (ADNC) may help distinguish limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) from ADNC.A comprehensive biomarker kit could aid enrollment in LATE-NC clinical trials.

High cortical iron is associated with the disruption of white matter tracts supporting cognitive function in healthy older adults.

Aging is associated with brain iron accumulation, which has been linked to cognitive decline. However, how brain iron affects the structure and function of cognitive brain networks remains unclear. Here, we explored the possibility that iron load in gray matter is associated with disruption of white matter (WM) microstructure within a network supporting cognitive function, in a cohort of 95 cognitively normal older adults (age range: 60-86). Functional magnetic resonance imaging was used to localize a set of brain regions involved in working memory and diffusion tensor imaging based probabilistic tractography was used to identify a network of WM tracts connecting the functionally defined regions. Brain iron concentration within these regions was evaluated using quantitative susceptibility mapping and microstructural properties were assessed within the identified tracts using neurite orientation dispersion and density imaging. Results indicated that high brain iron concentration was associated with low neurite density (ND) within the task-relevant WM network. Further, regional associations were observed such that brain iron in cortical regions was linked with lower ND in neighboring but not distant WM tracts. Our results provide novel evidence suggesting that age-related increases in brain iron concentration are associated with the disruption of WM tracts supporting cognitive function in normal aging.

MRI free water as a biomarker for cognitive performance: Validation in the MarkVCID consortium.

Introduction: To evaluate the clinical validity of free water (FW), a diffusion tensor imaging-based biomarker kit proposed by the MarkVCID consortium, by investigating the association between mean FW (mFW) and executive function. Methods: Baseline mFW was related to a baseline composite measure of executive function (EFC), adjusting for relevant covariates, in three MarkVCID sub-cohorts, and replicated in five, large, independent legacy cohorts. In addition, we tested whether baseline mFW predicted accelerated EFC score decline (mean follow-up time: 1.29 years). Results: Higher mFW was found to be associated with lower EFC scores in MarkVCID legacy and sub-cohorts (p-values < 0.05). In addition, higher baseline mFW was associated significantly with accelerated decline in EFC scores (p = 0.0026). Discussion: mFW is a sensitive biomarker of cognitive decline, providing a strong clinical rational for its use as a marker of white matter (WM) injury in multi-site observational studies and clinical trials of vascular cognitive impairment and dementia (VCID).

Multi-compartment diffusion magnetic resonance imaging models link tract-related characteristics with working memory performance in healthy older adults.

Multi-compartment diffusion MRI metrics [such as metrics from free water elimination diffusion tensor imaging (FWE-DTI) and neurite orientation dispersion and density imaging (NODDI)] may reflect more specific underlying white-matter tract characteristics than traditional, single-compartment metrics [i.e., metrics from Diffusion Tensor Imaging (DTI)]. However, it remains unclear if multi-compartment metrics are more closely associated with age and/or cognitive performance than single-compartment metrics. Here we compared the associations of single-compartment [Fractional Anisotropy (FA)] and multi-compartment diffusion MRI metrics [FWE-DTI metrics: Free Water Eliminated Fractional Anisotropy (FWE-FA) and Free Water (FW); NODDI metrics: Intracellular Volume Fraction (ICVF), Orientation Dispersion Index (ODI), and CSF-Fraction] with both age and working memory performance. A functional magnetic resonance imaging (fMRI) guided, white matter tractography approach was employed to compute diffusion metrics within a network of tracts connecting functional regions involved in working memory. Ninety-nine healthy older adults (aged 60-85) performed an in-scanner working memory task while fMRI was performed and also underwent multi-shell diffusion acquisition. The network of white matter tracts connecting functionally-activated regions was identified using probabilistic tractography. Diffusion metrics were extracted from skeletonized white matter tracts connecting fMRI activation peaks. Diffusion metrics derived from both single and multi-compartment models were associated with age (p s ≤ 0.011 for FA, FWE-FA, ICVF and ODI). However, only multi-compartment metrics, specifically FWE-FA (p = 0.045) and ICVF (p = 0.020), were associated with working memory performance. Our results suggest that while most current diffusion metrics are sensitive to age, several multi-compartment metrics (i.e., FWE-FA and ICVF) appear more sensitive to cognitive performance in healthy older adults.

Enlarged Perivascular Spaces Are Negatively Associated With Montreal Cognitive Assessment Scores in Older Adults.

Emerging evidence suggests that enlarged perivascular spaces (ePVS) may be a clinically significant neuroimaging marker of global cognitive function related to cerebral small vessel disease (cSVD). We tested this possibility by assessing the relationship between ePVS and both a standardized measure of global cognitive function, the Montreal Cognitive Assessment (MoCA), and an established marker of cSVD, white matter hyperintensity volume (WMH) volume. One hundred and eleven community-dwelling older adults (56-86) underwent neuroimaging and MoCA testing. Quantification of region-specific ePVS burden was performed using a previously validated visual rating method and WMH volumes were computed using the standard ADNI pipeline. Separate linear regression models were run with ePVS as a predictor of MoCA scores and whole brain WMH volume. Results indicated a negative association between MoCA scores and both total ePVS counts (P ≤ 0.001) and centrum semiovale ePVS counts (P ≤ 0.001), after controlling for other relevant cSVD variables. Further, WMH volumes were positively associated with total ePVS (P = 0.010), basal ganglia ePVS (P ≤ 0.001), and centrum semiovale ePVS (P = 0.027). Our results suggest that ePVS burden, particularly in the centrum semiovale, may be a clinically significant neuroimaging marker of global cognitive dysfunction related to cSVD.

Instrumental validation of free water, peak-width of skeletonized mean diffusivity, and white matter hyperintensities: MarkVCID neuroimaging kits.

Introduction: To describe the protocol and findings of the instrumental validation of three imaging-based biomarker kits selected by the MarkVCID consortium: free water (FW) and peak width of skeletonized mean diffusivity (PSMD), both derived from diffusion tensor imaging (DTI), and white matter hyperintensity (WMH) volume derived from fluid attenuation inversion recovery and T1-weighted imaging. Methods: The instrumental validation of imaging-based biomarker kits included inter-rater reliability among participating sites, test-retest repeatability, and inter-scanner reproducibility across three types of magnetic resonance imaging (MRI) scanners using intra-class correlation coefficients (ICC). Results: The three biomarkers demonstrated excellent inter-rater reliability (ICC >0.94, P-values < .001), very high agreement between test and retest sessions (ICC >0.98, P-values < .001), and were extremely consistent across the three scanners (ICC >0.98, P-values < .001). Discussion: The three biomarker kits demonstrated very high inter-rater reliability, test-retest repeatability, and inter-scanner reproducibility, offering robust biomarkers suitable for future multi-site observational studies and clinical trials in the context of vascular cognitive impairment and dementia (VCID).

Ironsmith: An automated pipeline for QSM-based data analyses.

Quantitative susceptibility mapping (QSM) is an MRI-based, computational method for anatomically localizing and measuring concentrations of specific biomarkers in tissue such as iron. Growing research suggests QSM is a viable method for evaluating the impact of iron overload in neurological disorders and on cognitive performance in aging. Several software toolboxes are currently available to reconstruct QSM maps from 3D GRE MR Images. However, few if any software packages currently exist that offer fully automated pipelines for QSM-based data analyses: from DICOM images to region-of-interest (ROI) based QSM values. Even less QSM-based software exist that offer quality control measures for evaluating the QSM output. Here, we address these gaps in the field by introducing and demonstrating the reliability and external validity of Ironsmith; an open-source, fully automated pipeline for creating and processing QSM maps, extracting QSM values from subcortical and cortical brain regions (89 ROIs) and evaluating the quality of QSM data using SNR measures and assessment of outlier regions on phase images. Ironsmith also features automatic filtering of QSM outlier values and precise CSF-only QSM reference masks that minimize partial volume effects. Testing of Ironsmith revealed excellent intra- and inter-rater reliability. Finally, external validity of Ironsmith was demonstrated via an anatomically selective relationship between motor performance and Ironsmith-derived QSM values in motor cortex. In sum, Ironsmith provides a freely-available, reliable, turn-key pipeline for QSM-based data analyses to support research on the impact of brain iron in aging and neurodegenerative disease.

Multi-vendor and multisite evaluation of cerebrovascular reactivity mapping using hypercapnia challenge.

Cerebrovascular reactivity (CVR), which measures the ability of cerebral blood vessels to dilate or constrict in response to vasoactive stimuli such as CO2 inhalation, is an important index of the brain's vascular health. Quantification of CVR using BOLD MRI with hypercapnia challenge has shown great promises in research and clinical studies. However, in order for it to be used as a potential imaging biomarker in large-scale and multi-site studies, the reliability of CO2-CVR quantification across different MRI acquisition platforms and researchers/raters must be examined. The goal of this report from the MarkVCID small vessel disease biomarkers consortium is to evaluate the reliability of CO2-CVR quantification in three studies. First, the inter-rater reliability of CO2-CVR data processing was evaluated by having raters from 5 MarkVCID sites process the same 30 CVR datasets using a cloud-based CVR data processing pipeline. Second, the inter-scanner reproducibility of CO2-CVR quantification was assessed in 10 young subjects across two scanners of different vendors. Third, test-retest repeatability was evaluated in 20 elderly subjects from 4 sites with a scan interval of less than 2 weeks. In all studies, the CO2 CVR measurements were performed using the fixed inspiration method, where the subjects wore a nose clip and a mouthpiece and breathed room air and 5% CO2 air contained in a Douglas bag alternatively through their mouth. The results showed that the inter-rater CoV of CVR processing was 0.08 ± 0.08% for whole-brain CVR values and ranged from 0.16% to 0.88% in major brain regions, with ICC of absolute agreement above 0.9959 for all brain regions. Inter-scanner CoV was found to be 6.90 ± 5.08% for whole-brain CVR values, and ranged from 4.69% to 12.71% in major brain regions, which are comparable to intra-session CoVs obtained from the same scanners on the same day. ICC of consistency between the two scanners was 0.8498 for whole-brain CVR and ranged from 0.8052 to 0.9185 across major brain regions. In the test-retest evaluation, test-retest CoV across different days was found to be 18.29 ± 17.12% for whole-brain CVR values, and ranged from 16.58% to 19.52% in major brain regions, with ICC of absolute agreement ranged from 0.6480 to 0.7785. These results demonstrated good inter-rater, inter-scanner, and test-retest reliability in healthy volunteers, and suggested that CO2-CVR has suitable instrumental properties for use as an imaging biomarker of cerebrovascular function in multi-site and longitudinal observational studies and clinical trials.

White Matter Hyperintensity Volume and Location: Associations With WM Microstructure, Brain Iron, and Cerebral Perfusion.

Cerebral white matter hyperintensities (WMHs) represent macrostructural brain damage associated with various etiologies. However, the relative contributions of various etiologies to WMH volume, as assessed via different neuroimaging measures, is not well-understood. Here, we explored associations between three potential early markers of white matter hyperintensity volume. Specifically, the unique variance in total and regional WMH volumes accounted for by white matter microstructure, brain iron concentration and cerebral blood flow (CBF) was assessed. Regional volumes explored were periventricular and deep regions. Eighty healthy older adults (ages 60-86) were scanned at 3 Tesla MRI using fluid-attenuated inversion recovery, diffusion tensor imaging (DTI), multi-echo gradient-recalled echo and pseudo-continuous arterial spin labeling sequences. In a stepwise regression model, DTI-based radial diffusivity accounted for significant variance in total WMH volume (adjusted R 2 change = 0.136). In contrast, iron concentration (adjusted R 2 change = 0.043) and CBF (adjusted R 2 change = 0.027) made more modest improvements to the variance accounted for in total WMH volume. However, there was an interaction between iron concentration and location on WMH volume such that iron concentration predicted deep (p = 0.034) but not periventricular (p = 0.414) WMH volume. Our results suggest that WM microstructure may be a better predictor of WMH volume than either brain iron or CBF but also draws attention to the possibility that some early WMH markers may be location-specific.

Healthy dietary intake moderates the effects of age on brain iron concentration and working memory performance.

Age-related brain iron accumulation is linked with oxidative stress, neurodegeneration and cognitive decline. Certain nutrients can reduce brain iron concentration in animal models, however, this association is not well established in humans. Moreover, it remains unknown if nutrition can moderate the effects of age on brain iron concentration and/or cognition. Here, we explored these issues in a sample of 73 healthy older adults (61-86 years old), while controlling for several factors such as age, gender, years of education, physical fitness and alcohol-intake. Quantitative susceptibility mapping was used for assessment of brain iron concentration and participants performed an N-Back paradigm to evaluate working memory performance. Nutritional-intake was assessed via a validated questionnaire. Nutrients were grouped into nutrition factors based on previous literature and factor analysis. One factor, comprised of vitamin E, lysine, DHA omega-3 and LA omega-6 PUFA, representing food groups such as nuts, healthy oils and fish, moderated the effects of age on both brain iron concentration and working memory performance, suggesting that these nutrients may slow the rate of brain iron accumulation and working memory declines in aging.

Cortical iron disrupts functional connectivity networks supporting working memory performance in older adults.

Excessive brain iron negatively affects working memory and related processes but the impact of cortical iron on task-relevant, cortical brain networks is unknown. We hypothesized that high cortical iron concentration may disrupt functional circuitry within cortical networks supporting working memory performance. Fifty-five healthy older adults completed an N-Back working memory paradigm while functional magnetic resonance imaging (fMRI) was performed. Participants also underwent quantitative susceptibility mapping (QSM) imaging for assessment of non-heme brain iron concentration. Additionally, pseudo continuous arterial spin labeling scans were obtained to control for potential contributions of cerebral blood volume and structural brain images were used to control for contributions of brain volume. Task performance was positively correlated with strength of task-based functional connectivity (tFC) between brain regions of the frontoparietal working memory network. However, higher cortical iron concentration was associated with lower tFC within this frontoparietal network and with poorer working memory performance after controlling for both cerebral blood flow and brain volume. Our results suggest that high cortical iron concentration disrupts communication within frontoparietal networks supporting working memory and is associated with reduced working memory performance in older adults.

Processing of Real-World, Dynamic Natural Stimuli in Autism is Linked to Corticobasal Function.

Many individuals with autism spectrum disorder (ASD) have been shown to perceive everyday sensory information differently compared to peers without autism. Research examining these sensory differences has primarily utilized nonnatural stimuli or natural stimuli using static photos with few having utilized dynamic, real-world nonverbal stimuli. Therefore, in this study, we used functional magnetic resonance imaging to characterize brain activation of individuals with high-functioning autism when viewing and listening to a video of a real-world scene (a person bouncing a ball) and anticipating the bounce. We investigated both multisensory and unisensory processing and hypothesized that individuals with ASD would show differential activation in (a) primary auditory and visual sensory cortical and association areas, and in (b) cortical and subcortical regions where auditory and visual information is integrated (e.g. temporal-parietal junction, pulvinar, superior colliculus). Contrary to our hypotheses, the whole-brain analysis revealed similar activation between the groups in these brain regions. However, compared to controls the ASD group showed significant hypoactivation in the left intraparietal sulcus and left putamen/globus pallidus. We theorize that this hypoactivation reflected underconnectivity for mediating spatiotemporal processing of the visual biological motion stimuli with the task demands of anticipating the timing of the bounce event. The paradigm thus may have tapped into a specific left-lateralized aberrant corticobasal circuit or loop involved in initiating or inhibiting motor responses. This was consistent with a dual "when versus where" psychophysical model of corticobasal function, which may reflect core differences in sensory processing of real-world, nonverbal natural stimuli in ASD. Autism Res 2020, 13: 539-549. © 2020 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: To understand how individuals with autism perceive the real-world, using magnetic resonance imaging we examined brain activation in individuals with autism while watching a video of someone bouncing a basketball. Those with autism had similar activation to controls in auditory and visual sensory brain regions, but less activation in an area that processes information about body movements and in a region involved in modulating movements. These areas are important for understanding the actions of others and developing social skills.

Education does not protect cognitive function from brain pathology in the ADNI 2 cohort.

Educational attainment is widely accepted as a cognitive reserve variable. However, few studies have demonstrated that education statistically moderates the effects of pathology on cognition. Here, we explored this issue in a sample of 441 Alzheimer's disease (AD) and mild cognitive impairment participants from the Alzheimer's Disease Neuroimaging Initiative cohort who had AD markers (Aß42, tau, structural brain volumes) at baseline and underwent cognitive testing at baseline and at 6-month, 12-month, and 24-month time points. An AD-related biomarker (atrophy/pathology) composite at baseline was developed using stepwise backward linear regression. Potential moderation effects of education on the relationship between AD biomarkers and cognition were explored using linear mixed models. Education was positively correlated with cognition, and biomarkers were negatively correlated with cognition, across domains and diagnostic groups. However, education generally did not moderate the effects of biomarkers on baseline or longitudinal cognition. Our results do not support the hypothesis that education protects cognitive function from brain pathology in the Alzheimer's Disease Neuroimaging Initiative cohort, questioning its accepted status as a reserve variable.

Sleep Validity of a Non-Contact Bedside Movement and Respiration-Sensing Device.

STUDY OBJECTIVES: To assess the sleep detection and staging validity of a non-contact, commercially available bedside bio-motion sensing device (S+, ResMed) and evaluate the impact of algorithm updates. METHODS: Polysomnography data from 27 healthy adult participants was compared epoch-by-epoch to synchronized data that were recorded and staged by actigraphy and S+. An update to the S+ algorithm (common in the rapidly evolving commercial sleep tracker industry) permitted comparison of the original (S+V1) and updated (S+V2) versions. RESULTS: Sleep detection accuracy by S+V1 (93.3%), S+V2 (93.8%), and actigraphy (96.0%) was high; wake detection accuracy by each (69.6%, 73.1%, and 47.9%, respectively) was low. Higher overall S+ specificity, compared to actigraphy, was driven by higher accuracy in detecting wake before sleep onset (WBSO), which differed between S+V2 (90.4%) and actigraphy (46.5%). Stage detection accuracy by the S+ did not exceed 67.6% (for stage N2 sleep, by S+V2) for any stage. Performance is compared to previously established variance in polysomnography scored by humans: a performance standard which commercial devices should ideally strive to reach. CONCLUSIONS: Similar limitations in detecting wake after sleep onset (WASO) were found for the S+ as have been previously reported for actigraphy and other commercial sleep tracking devices. S+ WBSO detection was higher than actigraphy, and S+V2 algorithm further improved WASO accuracy. Researchers and clinicians should remain aware of the potential for algorithm updates to impact validity. COMMENTARY: A commentary on this article appears in this issue on page 935.

White Matter Hyperintensity Regression: Comparison of Brain Atrophy and Cognitive Profiles with Progression and Stable Groups.

Subcortical white matter hyperintensities (WMHs) in the aging population frequently represent vascular injury that may lead to cognitive impairment. WMH progression is well described, but the factors underlying WMH regression remain poorly understood. A sample of 351 participants from the Alzheimer's Disease Neuroimaging Initiative 2 (ADNI2) was explored who had WMH volumetric quantification, structural brain measures, and cognitive measures (memory and executive function) at baseline and after approximately 2 years. Selected participants were categorized into three groups based on WMH change over time, including those that demonstrated regression (n = 96; 25.5%), stability (n = 72; 19.1%), and progression (n = 209; 55.4%). There were no significant differences in age, education, sex, or cognitive status between groups. Analysis of variance demonstrated significant differences in atrophy between the progression and both regression (p = 0.004) and stable groups (p = 0.012). Memory assessments improved over time in the regression and stable groups but declined in the progression group (p = 0.003; p = 0.018). WMH regression is associated with decreased brain atrophy and improvement in memory performance over two years compared to those with WMH progression, in whom memory and brain atrophy worsened. These data suggest that WMHs are dynamic and associated with changes in atrophy and cognition.

Breastfeeding Duration Is Associated with Regional, but Not Global, Differences in White Matter Tracts.

Extended breastfeeding through infancy confers benefits on neurocognitive performance and intelligence tests, though few have examined the biological basis of these effects. To investigate correlations with breastfeeding, we examined the major white matter tracts in 4-8 year-old children using diffusion tensor imaging and volumetric measurements of the corpus callosum. We found a significant correlation between the duration of infant breastfeeding and fractional anisotropy scores in left-lateralized white matter tracts, including the left superior longitudinal fasciculus and left angular bundle, which is indicative of greater intrahemispheric connectivity. However, in contrast to expectations from earlier studies, no correlations were observed with corpus callosum size, and thus no correlations were observed when using such measures of global interhemispheric white matter connectivity development. These findings suggest a complex but significant positive association between breastfeeding duration and white matter connectivity, including in pathways known to be functionally relevant for reading and language development.