Niousha Bolandzadeh1, Teresa Liu-Ambrose2, Howard Aizenstein3, Tamara Harris4, Lenore Launer4, Kristine Yaffe5, Stephen B Kritchevsky6, Anne Newman7, Caterina Rosano8. 1. Aging, Mobility, and Cognitive Neuroscience Laboratory, Department of Physical Therapy, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada; Brain Research Centre, University of British Columbia, Vancouver, BC, Canada; Experimental Medicine Graduate Program, Department of Medicine, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada. 2. Aging, Mobility, and Cognitive Neuroscience Laboratory, Department of Physical Therapy, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada; Brain Research Centre, University of British Columbia, Vancouver, BC, Canada. 3. Geriatric Psychiatry Neuroimaging Laboratory, Faculty of Medicine, University of Pittsburgh, Pittsburgh, PA, USA. 4. Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Bethesda, MD, USA. 5. Department of Psychiatry, University of California, San Francisco, CA, USA. 6. Sticht Center on Aging, Wake Forest School of Medicine, Winston-Salem, NC, USA. 7. Center for Aging and Population Health, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA. 8. Center for Aging and Population Health, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: RosanoC@edc.pitt.edu.
Abstract
IMPORTANCE: Cerebral white matter hyperintensities (WMHs) are involved in the evolution of impaired mobility and executive functions. Executive functions and mobility are also associated. Thus, WMHs may impair mobility directly, by disrupting mobility-related circuits, or indirectly, by disrupting circuits responsible for executive functions. Understanding the mechanisms underlying impaired mobility in late life will increase our capacity to develop effective interventions. OBJECTIVE: To identify regional WMHs most related to slower gait and to examine whether these regional WMHs directly impact mobility, or indirectly by executive functions. DESIGN: Cross-sectional study. Twenty-one WMH variables (i.e., total WMH volume and WMHs in 20 tracts), gait speed, global cognition (Modified Mini-Mental State Examination; 3MS), and executive functions and processing speed (Digit-Symbol Substitution Test; DSST) were assessed. An L1-L2 regularized regression (i.e., Elastic Net model) identified the WMH variables most related to slower gait. Multivariable linear regression models quantified the association between these WMH variables and gait speed. Formal tests of mediation were also conducted. SETTING: Community-based sample. PARTICIPANTS: Two hundred fifty-three adults (mean age: 83years, 58% women, 41% black). MAIN OUTCOME MEASURE: Gait speed. RESULTS: In older adults with an average gait speed of 0.91m/sec, total WMH volume, WMHs located in the right anterior thalamic radiation (ATRR) and frontal corpuscallosum (CCF) were most associated with slower gait. There was a >10% slower gait for each standard deviation of WMH in CCF, ATRR or total brain (standardized beta in m/sec [p value]: -0.11 [p=0.046], -0.15 [p=0.007] and -0.14 [p=0.010], respectively). These associations were substantially and significantly attenuated after adjustment for DSST. This effect was stronger for WMH in CCF than for ATRR or total WMH (standardized beta in m/sec [p value]: -0.07 [p=0.190], -0.12 [p=0.024] and -0.10 [p=0.049], respectively). Adjustment for 3MS did not change these associations. The mediation analyses also found that DSST significantly mediated the associations between WMHs and gait speed. Our models were adjusted for age, sex, BMI, quadriceps strength, years of education, standing height, and prevalent hypertension. CONCLUSION: The impact, direct or indirect, of WMHs on gait speed depended on their location and was mediated by executive function. Thus, multi-faceted interventions targeting executive control functions as well as motor functions, such as balance and strength training, are candidates to the maintenance of mobility across the lifespan.
IMPORTANCE: Cerebral white matter hyperintensities (WMHs) are involved in the evolution of impaired mobility and executive functions. Executive functions and mobility are also associated. Thus, WMHs may impair mobility directly, by disrupting mobility-related circuits, or indirectly, by disrupting circuits responsible for executive functions. Understanding the mechanisms underlying impaired mobility in late life will increase our capacity to develop effective interventions. OBJECTIVE: To identify regional WMHs most related to slower gait and to examine whether these regional WMHs directly impact mobility, or indirectly by executive functions. DESIGN: Cross-sectional study. Twenty-one WMH variables (i.e., total WMH volume and WMHs in 20 tracts), gait speed, global cognition (Modified Mini-Mental State Examination; 3MS), and executive functions and processing speed (Digit-Symbol Substitution Test; DSST) were assessed. An L1-L2 regularized regression (i.e., Elastic Net model) identified the WMH variables most related to slower gait. Multivariable linear regression models quantified the association between these WMH variables and gait speed. Formal tests of mediation were also conducted. SETTING: Community-based sample. PARTICIPANTS: Two hundred fifty-three adults (mean age: 83years, 58% women, 41% black). MAIN OUTCOME MEASURE: Gait speed. RESULTS: In older adults with an average gait speed of 0.91m/sec, total WMH volume, WMHs located in the right anterior thalamic radiation (ATRR) and frontal corpuscallosum (CCF) were most associated with slower gait. There was a >10% slower gait for each standard deviation of WMH in CCF, ATRR or total brain (standardized beta in m/sec [p value]: -0.11 [p=0.046], -0.15 [p=0.007] and -0.14 [p=0.010], respectively). These associations were substantially and significantly attenuated after adjustment for DSST. This effect was stronger for WMH in CCF than for ATRR or total WMH (standardized beta in m/sec [p value]: -0.07 [p=0.190], -0.12 [p=0.024] and -0.10 [p=0.049], respectively). Adjustment for 3MS did not change these associations. The mediation analyses also found that DSST significantly mediated the associations between WMHs and gait speed. Our models were adjusted for age, sex, BMI, quadriceps strength, years of education, standing height, and prevalent hypertension. CONCLUSION: The impact, direct or indirect, of WMHs on gait speed depended on their location and was mediated by executive function. Thus, multi-faceted interventions targeting executive control functions as well as motor functions, such as balance and strength training, are candidates to the maintenance of mobility across the lifespan.
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