Effect of Isocaloric, Time-Restricted Eating on Body Weight in Adults With Obesity : A Randomized Controlled Trial.

BACKGROUND: Time-restricted eating (TRE) lowers body weight in many studies. Whether TRE induces weight loss independent of reductions in calorie intake, as seen in rodent studies, is unknown. OBJECTIVE: To determine the effect of TRE versus a usual eating pattern (UEP) on body weight in the setting of stable caloric intake. DESIGN: Randomized, isocaloric feeding study. (ClinicalTrials.gov: NCT03527368). SETTING: Clinical research unit. PARTICIPANTS: Adults with obesity and prediabetes or diet-controlled diabetes. INTERVENTION: Participants were randomly assigned 1:1 to TRE (10-hour eating window, 80% of calories before 1 p.m.) or UEP (≤16-hour window, ≥50% of calories after 5 p.m.) for 12 weeks. Both groups had the same nutrient content and were isocaloric with total calories determined at baseline. MEASUREMENTS: Primary outcome was change in body weight at 12 weeks. Secondary outcomes were fasting glucose, homeostatic model assessment for insulin resistance (HOMA-IR), glucose area under the curve by oral glucose tolerance test, and glycated albumin. We used linear mixed models to evaluate the effect of interventions on outcomes. RESULTS: All 41 randomly assigned participants (mean age, 59 years; 93% women; 93% Black race; mean BMI, 36 kg/m2) completed the intervention. Baseline weight was 95.6 kg (95% CI, 89.6 to 101.6 kg) in the TRE group and 103.7 kg (CI, 95.3 to 112.0 kg) in the UEP group. At 12 weeks, weight decreased by 2.3 kg (CI, 1.0 to 3.5 kg) in the TRE group and by 2.6 kg (CI, 1.5 to 3.7 kg) in the UEP group (average difference TRE vs. UEP, 0.3 kg [CI, -1.2 to 1.9 kg]). Change in glycemic measures did not differ between groups. LIMITATION: Small, single-site study; baseline differences in weight by group. CONCLUSION: In the setting of isocaloric eating, TRE did not decrease weight or improve glucose homeostasis relative to a UEP, suggesting that any effects of TRE on weight in prior studies may be due to reductions in caloric intake. PRIMARY FUNDING SOURCE: American Heart Association.

Sensory and motor deficits as contributors to early cognitive impairment.

INTRODUCTION: Age-related sensory and motor impairment are associated with risk of dementia. No study has examined the joint associations of multiple sensory and motor measures on prevalence of early cognitive impairment (ECI). METHODS: Six hundred fifty participants in the Baltimore Longitudinal Study of Aging completed sensory and motor function tests. The association between sensory and motor function and ECI was examined using structural equation modeling with three latent factors corresponding to multisensory, fine motor, and gross motor function. RESULTS: The multisensory, fine, and gross motor factors were all correlated (r = 0.74 to 0.81). The odds of ECI were lower for each additional unit improvement in the multisensory (32%), fine motor (30%), and gross motor factors (12%). DISCUSSION: The relationship between sensory and motor impairment and emerging cognitive impairment may guide future intervention studies aimed at preventing and/or treating ECI. HIGHLIGHTS: Sensorimotor function and early cognitive impairment (ECI) prevalence were assessed via structural equation modeling. The degree of fine and gross motor function is associated with indicators of ECI. The degree of multisensory impairment is also associated with indicators of ECI.

Toward a Social Bioethics Through Interpretivism: A Framework for Healthcare Ethics.

Recent global events demonstrate that analytical frameworks to aid professionals in healthcare ethics must consider the pervasive role of social structures in the emergence of bioethical issues. To address this, the authors propose a new sociologically informed approach to healthcare ethics that they term "social bioethics." Their approach is animated by the interpretive social sciences to highlight how social structures operate vis-à-vis the everyday practices and moral reasoning of individuals, a phenomenon known as social discourse. As an exemplar, the authors use social bioethics to reframe common ethical issues in psychiatric services and discuss potential implications. Lastly, the authors discuss how social bioethics illuminates the ways healthcare ethics consultants in both policy and clinical decision-making participate in and shape broader social, political, and economic systems, which then cyclically informs the design and delivery of healthcare.

Pain, but not Physical Activity, is Associated with Gray Matter Volume Differences in Gulf War Veterans with Chronic Pain.

Chronic musculoskeletal pain (CMP) is a significant burden for Persian Gulf War Veterans (GWV), yet the causes are poorly understood. Brain structure abnormalities are observed in GWV, however relationships with modifiable lifestyle factors such as physical activity (PA) are unknown. We evaluated gray matter volumes and associations with symptoms, PA, and sedentary time in GWV with and without CMP. Ninety-eight GWV (10 females) with CMP and 56 GWV (7 females) controls completed T1 weighted magnetic resonance imaging, pain and fatigue symptom questionnaires, and PA measurement via actigraphy. Regional gray matter volumes were analyzed using voxel-based morphometry and were compared across groups using analysis of covariance. Separate multiple linear regression models were used to test associations between PA intensities, sedentary time, symptoms, and gray matter volumes. Family-wise cluster error rates were used to control for multiple comparisons (α=0.05). GWV with CMP reported greater pain and fatigue symptoms, worse mood, and engaged in less moderate-to-vigorous PA and more sedentary time than healthy GWV (all p<0.05). GWV with CMP had smaller gray matter volumes in the bilateral insula and larger volumes in the frontal pole (p<0.05adjusted). Gray matter volumes in the left insula were associated with pain symptoms (rpartial=0.26, -0.29; p<0.05adjusted). No significant associations were observed for either PA or sedentary time (p>0.05adjusted). GWV with CMP had smaller gray matter volumes within a critical brain region of the descending pain processing network and larger volumes within brain regions associated with pain sensation and affective processing which may reflect pain chronification.Significance Statement:The pathophysiology of chronic pain in Gulf War Veterans is understudied and not well understood. In a large sample of Gulf War Veterans, we report Veterans with chronic musculoskeletal pain have smaller gray matter volumes in brain regions associated with pain regulation and larger volumes in regions associated with pain sensitivity compared to otherwise healthy Gulf War Veterans. Gray matter volumes in regions of pain regulation were significantly associated with pain symptoms and encompassed the observed group brain volume differences. These results are suggestive of deficient pain modulation that may contribute to pain chronification.

Wrist-Worn Accelerometry, Aging, and Gait Speed in the Baltimore Longitudinal Study of Aging.

Wrist-worn accelerometry metrics are not well defined in older adults. Accelerometry data from 720 participants (mean age 70 years, 55% women) were summarized into (a) total activity counts per day, (b) active minutes per day, (c) active bouts per day, and (d) activity fragmentation (the reciprocal of the mean active bout length). Linear regression and mixed-effects models were utilized to estimate associations between age and gait speed with wrist accelerometry. Activity counts per day, daily active minutes per day, and active bouts per day were negatively associated with age among all participants, while positive associations with activity fragmentation were only observed among those ≥65 years. More activity counts, more daily active minutes, and lower activity fragmentation were associated with faster gait speed. There were baseline age interactions with annual changes in total activity counts per day, active minutes per day, and activity fragmentation (Baseline age × Time, p < .01 for all). These results help define and characterize changes in wrist-based physical activity patterns among older adults.

Impact of Time in Motion on Blood Pressure Regulation Among Patients with Metabolic Syndrome.

PURPOSE OF REVIEW: This review assessed recent evidence on the association between objectively measured physical activity from wearable accelerometers and blood pressure (BP) in participants with metabolic syndrome (MetS). RECENT FINDINGS: Results directly related to BP were mixed, with some studies showing positive associations and others showing null results. Importantly, several studies noted that participants with MetS demonstrated greater improvements in components of MetS after engaging in higher amounts of daily physical activity. Although this suggests greater volume of physical activity may be a means to partially mitigate hypertension in those with MetS, it remains unclear whether physical activity or inactivity (i.e., sedentary behavior) is more strongly associated with MetS. Although there may be benefit to greater volumes of daily PA among hypertensive patients with MetS, more research is needed to quantify and define the amount of daily activity needed to improve health and refine clinical recommendations. Moreover, although the evidence for improving components of MetS through engaging in physical activity is high, the amount and type(s) of physical activity needed to achieve these benefits is unclear.

Employing CRISPR-Cas9 to Generate CD133 Synthetic Lethal Melanoma Stem Cells.

Malignant melanoma is a lethal skin cancer containing melanoma-initiating cells (MIC) implicated in tumorigenesis, invasion, and drug resistance, and is characterized by the elevated expression of stem cell markers, including CD133. The siRNA knockdown of CD133 enhances apoptosis induced by the MEK inhibitor trametinib in melanoma cells. This study investigates the underlying mechanisms of CD133's anti-apoptotic activity in patient-derived BAKP and POT cells, harboring difficult-to-treat NRASQ61K and NRASQ61R drivers, after CRISPR-Cas9 CD133 knockout or Dox-inducible expression of CD133. MACS-sorted CD133(+) BAKP cells were conditionally reprogrammed to derive BAKR cells with sustained CD133 expression and MIC features. Compared to BAKP, CD133(+) BAKR exhibit increased cell survival and reduced apoptosis in response to trametinib or the chemotherapeutic dacarbazine (DTIC). CRISPR-Cas9-mediated CD133 knockout in BAKR cells (BAKR-KO) re-sensitized cells to trametinib. CD133 knockout in BAKP and POT cells increased trametinib-induced apoptosis by reducing anti-apoptotic BCL-xL, p-AKT, and p-BAD and increasing pro-apoptotic BAX. Conversely, Dox-induced CD133 expression diminished apoptosis in both trametinib-treated cell lines, coincident with elevated p-AKT, p-BAD, BCL-2, and BCL-xL and decreased activation of BAX and caspases-3 and -9. AKT1/2 siRNA knockdown or inhibition of BCL-2 family members with navitoclax (ABT-263) in BAKP-KO cells further enhanced caspase-mediated apoptotic PARP cleavage. CD133 may therefore activate a survival pathway where (1) increased AKT phosphorylation and activation induces (2) BAD phosphorylation and inactivation, (3) decreases BAX activation, and (4) reduces caspases-3 and -9 activity and caspase-mediated PARP cleavage, leading to apoptosis suppression and drug resistance in melanoma. Targeting nodes of the CD133, AKT, or BCL-2 survival pathways with trametinib highlights the potential for combination therapies for NRAS-mutant melanoma stem cells for the development of more effective treatments for patients with high-risk melanoma.

Transcranial Color-Coded Doppler Cerebral Hemodynamics Following Aerobic Exercise Training: Outcomes From a Pilot Randomized Clinical Trial.

Introduction: An active lifestyle with regular exercise is thought to decrease or delay the onset of Alzheimer dementia through increasing blood flow to the brain. We examined the mean flow velocity (MFV) and pulsatility index (PI) in the middle cerebral arteries of individuals randomized into two groups-a Usual Physical Activity (UPA) group and an Enhanced Physical Activity (EPA) exercise intervention group-to determine if exercise training is related to changes in cerebral blood flow. Methods: We examined 23 participants, randomized into a UPA group (n=12) and an EPA group (n=11), with transcranial color-coded Doppler (TCCD) and cardiorespiratory fitness (VO2peak, mL/kg/min) testing at baseline and following a 26-week intervention. TCCD was used to measure MFV and PI. Participants in the EPA group completed supervised aerobic exercise training for 26 weeks. Kendall's tau b correlation was used to examine relationships between variables. The Wilcoxon Rank Sum tests were used to examine changes between the UPA and EPA groups. Results: There was no significant change in MFV or PI in the UPA group or the EPA group (p-values >0.05) between baseline and 26 weeks; the change between the UPA and EPA groups was also not significant (p=0.603). There was no evidence of an association between change in VO2peak and change in MFV or PI (all p-values >0.05). Participants in the EPA group significantly increased their VO2peak compared to the UPA group (p=0.027). Conclusion: This study did not demonstrate evidence of a significant change in the MFV in the middle cerebral arteries or evidence of a significant change in the PI between UPA and EPA groups. Future studies should be performed in larger cohorts and should consider use of personalized exercise programs to maximize understanding of how cerebrovascular hemodynamics change in structure and function with exercise for adults at risk for Alzheimer dementia.

Definitions of Community for Individuals with Serious Mental Illnesses: Implications for Community Integration and Recovery.

While recent work on community integration for individuals with serious mental illnesses (SMIs) has focused on the multi-dimensionality of community integration, it has not been fully rooted in how consumers define and experience communities for themselves. Guided by symbolic interactionism theory, the goal of the present study is to explore definitions of community as provided by individuals with SMIs, and to incorporate those definitions into a theoretical framework of community to inform community integration efforts in the context of mental health services and recovery. Semi-structured interviews were conducted between November 2017 and September 2018 with 90 racially/ethnically diverse participants who were 18 years and older with an SMI and receiving community mental health services. Interviews were audio-recorded, transcribed, and analyzed using ResearchTalk's "Sort and Sift, Think and Shift" methodology. Themes derived from participants' definitions of community included a structural aspect of people and places; a functional aspect of socializing, helping and receiving resources; and an experiential aspect of shared struggles and experiences, finding safety, and identifying with others. To this end, we propose a Structural, Functional and Experiential (SFE) model of community. The SFE model of community provides a conceptual framework and guidance for clinicians, researchers, policy makers and service stakeholders regarding the complexity and variability of community for their consumers, which is essential to their recovery. Application of the SFE framework for assessment and intervention is discussed.

Neural consequences of post-exertion malaise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

Post exertion malaise is one of the most debilitating aspects of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, yet the neurobiological consequences are largely unexplored. The objective of the study was to determine the neural consequences of acute exercise using functional brain imaging. Fifteen female Myalgic Encephalomyelitis/Chronic Fatigue Syndrome patients and 15 healthy female controls completed 30min of submaximal exercise (70% of peak heart rate) on a cycle ergometer. Symptom assessments (e.g. fatigue, pain, mood) and brain imaging data were collected one week prior to and 24h following exercise. Functional brain images were obtained during performance of: 1) a fatiguing cognitive task - the Paced Auditory Serial Addition Task, 2) a non-fatiguing cognitive task - simple number recognition, and 3) a non-fatiguing motor task - finger tapping. Symptom and exercise data were analyzed using independent samples t-tests. Cognitive performance data were analyzed using mixed-model analysis of variance with repeated measures. Brain responses to fatiguing and non-fatiguing tasks were analyzed using linear mixed effects with cluster-wise (101-voxels) alpha of 0.05. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome patients reported large symptom changes compared to controls (effect size ≥0.8, p<0.05). Patients and controls had similar physiological responses to exercise (p>0.05). However, patients exercised at significantly lower Watts and reported greater exertion and leg muscle pain (p<0.05). For cognitive performance, a significant Group by Time interaction (p<0.05), demonstrated pre- to post-exercise improvements for controls and worsening for patients. Brain responses to finger tapping did not differ between groups at either time point. During number recognition, controls exhibited greater brain activity (p<0.05) in the posterior cingulate cortex, but only for the pre-exercise scan. For the Paced Serial Auditory Addition Task, there was a significant Group by Time interaction (p<0.05) with patients exhibiting increased brain activity from pre- to post-exercise compared to controls bilaterally for inferior and superior parietal and cingulate cortices. Changes in brain activity were significantly related to symptoms for patients (p<0.05). Acute exercise exacerbated symptoms, impaired cognitive performance and affected brain function in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome patients. These converging results, linking symptom exacerbation with brain function, provide objective evidence of the detrimental neurophysiological effects of post-exertion malaise.

Diastereoselective synthesis of γ- and δ-lactams from imines and sulfone-substituted anhydrides.

Sulfone-substituted γ- and δ-lactams have been prepared in a single step with high diastereoselectivity. Sulfonylglutaric anhydrides produce intermediates that readily decarboxylate to provide δ-lactams with high diastereoselectivity. Substituents at the 3- or 4-position of the glutaric anhydride induce high levels of stereocontrol. Sulfonylsuccinic anhydrides produce intermediate carboxylic acids that can be trapped as methyl esters or allowed to decarboxylate under mild conditions. This method has been applied to a short synthesis of the pyrrolizidine alkaloid (±)-isoretronecanol.

Physical Activity Intensity and Risk of Dementia.

INTRODUCTION: Regular participation in aerobic physical activity is associated with a reduced risk of dementia. It is currently unclear whether this association is due to the total volume or intensity of physical activity. METHODS: This prospective cohort study analyzed 386,486 adults from the UK Biobank who were free of dementia and self-reported >0 minutes of moderate-to-vigorous intensity physical activity (MVPA) at baseline (2007-2010). Participants were categorized as performing 0%, >0%-30%, or >30% of their total MVPA in vigorous activity (VPA). Cox proportional hazards regression models were used to examine the associations between categories of VPA and incident dementia while adjusting for sociodemographic and lifestyle factors including total MVPA. Analyses were performed in 2022. RESULTS: Over an average follow-up of 12.0 (1.7) years, there were 5,177 (1.3%) cases of dementia. Compared to the group reporting 0% VPA, the hazard ratios (95% confidence intervals) of dementia for the groups reporting >0%-30% and >30% VPA were 0.73 (0.68-0.78) and 0.81 (0.75-0.87), respectively, in the fully adjusted model. In a joint analysis, reporting some VPA was associated with a reduced risk of dementia regardless of meeting the aerobic physical activity guidelines (HR=0.78 [0.72-0.85]) or not (HR=0.76 [0.60-0.98]), while meeting the aerobic physical activity guidelines alone without VPA was not associated with incident dementia (HR=0.98 [0.90-1.07]), compared to the group that did not meet the guidelines and reported no VPA. CONCLUSIONS: These results suggest that engaging in VPA as part of MVPA is associated with a lower risk of dementia.

Shared and Distinct Associations of Manual Dexterity and Gross Motor Function With Brain Atrophy.

BACKGROUND: Poor motor function is associated with brain atrophy and cognitive impairment. Less is known about the relationship between motor domains and brain atrophy and whether associations are affected by cerebrovascular burden and/or physical activity. METHODS: We analyzed data from 726 Baltimore Longitudinal Study of Aging participants (mean age 70.6 ±â€…10.1 years, 56% women, 27% Black), 525 of whom had repeat MRI scans over an average of 5.0 ±â€…2.1 years. Two motor domains, manual dexterity and gross motor, were operationalized as latent variables. Associations between the latent variables and cortical and subcortical brain volumes of interest were examined using latent growth curve modeling, adjusted for demographics, white matter hyperintensities, and physical activity. RESULTS: Both higher manual dexterity and gross motor function were cross-sectionally associated with smaller ventricular volume and greater white matter volumes in the frontal, parietal, and temporal lobes (all p < .05). Manual dexterity was also cross-sectionally associated with parietal gray matter (B = 0.14; 95% CI: 0.05, 0.23), hippocampus (B = 0.10; 95% CI: 0.01, 0.20), postcentral gyrus (B = 0.11; 95% CI: 0.01, 0.20), and occipital white matter (B = 0.10; 95% CI: 0.01, 0.21) volumes, and gross motor function with temporal gray matter volume (B = 0.16; 95% CI: 0.05, 0.26). Longitudinally, both higher manual dexterity and gross motor function were associated with less temporal white matter and occipital gray matter atrophy (all p < .05). Manual dexterity was also associated with a slower rate of ventricular enlargement (B = -0.17; 95% CI: -0.29, -0.05) and less atrophy of occipital white matter (B = 0.39; 95% CI: 0.04, 0.71). CONCLUSIONS: Among cognitively normal middle- and older-aged adults, manual dexterity and gross motor function exhibited shared as well as distinct associations with brain atrophy over time.

Differences in Daily Physical Activity by Alzheimer's Risk Markers Among Older Adults.

BACKGROUND: Daily physical activity patterns differ by Alzheimer's disease (AD) status and might signal cognitive risk. It is critical to understand whether patterns are disrupted early in the AD pathological process. Yet, whether established AD risk markers (ß-amyloid [Aß] or apolipoprotein E-ε4 [APOE-ε4]) are associated with differences in objectively measured activity patterns among cognitively unimpaired older adults is unclear. METHODS: Wrist accelerometry, brain Aß (+/-), and APOE-ε4 genotype were collected in 106 (Aß) and 472 (APOE-ε4) participants (mean age 76 [standard deviation{SD}: 8.5) or 75 [SD: 9.2] years, 60% or 58% women) in the Baltimore Longitudinal Study of Aging. Adjusted linear and function-on-scalar regression models examined whether Aß or APOE-ε4 status was cross-sectionally associated with activity patterns (amount, variability, or fragmentation) overall and by time of day, respectively. Differences in activity patterns by combinations of Aß and APOE-ε4 status were descriptively examined (n = 105). RESULTS: There were no differences in any activity pattern by Aß or APOE-ε4 status overall. Aß+ was associated with lower total amount and lower within-day variability of physical activity overnight and early evening, and APOE-ε4 carriers had higher total amount of activity in the evening and lower within-day variability of activity in the morning. Diurnal curves of activity were blunted among those with Aß+ regardless of APOE-ε4 status, but only when including older adults with mild cognitive impairment/dementia. CONCLUSIONS: Aß+ in cognitively unimpaired older adults might manifest as lower amount and variability of daily physical activity, particularly during overnight/evening hours. Future research is needed to examine changes in activity patterns in larger samples and by other AD biomarkers.

Relationship between skeletal mitochondrial function and digital markers of free-living physical activity in older adults.

This study examined the association between in vivo skeletal mitochondrial function and digital free-living physical activity patterns-a measure that summarizes biological, phenotypic, functional, and environmental effects on mobility. Among 459 participants (mean age 68 years; 55% women) in the Baltimore Longitudinal Study of Aging, mitochondrial function was quantified as skeletal muscle oxidative capacity via post-exercise phosphocreatine recovery rate (τPCr) in the vastus lateralis muscle of the left thigh, using 31P magnetic resonance spectroscopy. Accelerometry was collected using a 7-day, 24-h wrist-worn protocol and summarized into activity amount, intensity, endurance, and accumulation patterning metrics. Linear regression, two-part linear and logistic (bout analyses), and linear mixed effects models (time-of-day analyses) were used to estimate associations between τPCr and each physical activity metric. Interactions by age, sex, and gait speed were tested. After covariate adjustment, higher τPCr (or poorer mitochondrial function) was associated with lower activity counts/day (ß = - 6593.7, SE = 2406.0; p = 0.006) and activity intensity (- 81.5 counts, SE = 12.9; p < 0.001). For activity intensity, the magnitude of association was greater for men and those with slower gait speed (interaction p < 0.02 for both). Conversely, τPCr was not associated with daily active minutes/day (p = 0.15), activity fragmentation (p = 0.13), or endurance at any bout length (p > 0.05 for all). Time-of-day analyses show participants with high τPCr were less active from 6:00 a.m. to 12:00 a.m. than those with low τPCr. Results indicate that poorer skeletal mitochondrial function is primarily associated with lower engagement in high intensity activities. Our findings help define the connection between laboratory-measured mitochondrial function and real-world physical activity behavior.

Renewed calls for abortion-related research in the post-Roe era.

Nearly 50 years after Roe versus Wade, the United States Supreme Court's decision in Dobbs versus Jackson Women's Health Organization unraveled the constitutional right to abortion, allowing individual states to severely restrict or ban the procedure. In response, leading medical, public health, and community organizations have renewed calls for research to elucidate and address the burgeoning social and medical consequences of new abortion restrictions. Abortion research not only includes studies that establish the safety, quality, and efficacy of evidence-based abortion care protocols, but also encompasses studies on the availability of abortion care, the consequences of being denied an abortion, and the legal and social burdens surrounding abortion. The urgency of these calls for new evidence underscores the importance of ensuring that research in this area is conducted in an ethical and respectful manner, cognizant of the social, political, and structural conditions that shape reproductive health inequities and impact each stage of research-from protocol design to dissemination of findings. Research ethics relates to the moral principles undergirding the design and execution of research projects, and concerns itself with the technicalities of ethical questions related to the research process, such as informed consent, power relations, and confidentiality. Critical insights and reflections from reproductive justice, community engagement, and applied ethics frameworks have bolstered existing research ethics scholarship and discourse by underscoring the importance of meaningful engagement with community stakeholders-bringing attention to overlapping structures of oppression, including racism, sexism, and ways that these structures are perpetuated in the research process.

Walking energetics and white matter hyperintensities in mid-to-late adulthood.

INTRODUCTION: White matter hyperintensities (WMHs) increase with age and contribute to cognitive and motor function decline. Energy costs for mobility worsen with age, as the energetic cost of walking increases and energetic capacity declines. We examined the cross-sectional associations of multiple measures of walking energetics with WMHs in mid- to late-aged adults. METHODS: A total of 601 cognitively unimpaired adults (mean age 66.9 ± 15.3 years, 54% women) underwent brain magnetic resonance imaging scans and completed standardized slow- and peak-paced walking assessments with metabolic measurement (V̇O2). T1-weighted scans and fluid-attenuated inversion recovery images were used to quantify WMHs. Separate multivariable linear regression models examined associations adjusted for covariates. RESULTS: Lower slow-paced V̇O2 (B = 0.07; P = 0.030), higher peak-paced V̇O2 (B = -0.10; P = 0.007), and lower cost-to-capacity ratio (B = .12; P < 0.0001) were all associated with lower WMH volumes. DISCUSSION: The cost-to-capacity ratio, which describes the percentage of capacity required for ambulation, was the walking energetic measure most strongly associated with WMHs.