Structural neural correlates of impaired mobility and subsequent decline in executive functions: a 12-month prospective study.

Impaired mobility, such as falls, may be an early biomarker of subsequent cognitive decline and is associated with subclinical alterations in both brain structure and function. In this 12-month prospective study, we examined whether there are volumetric differences in gray matter and subcortical regions, as well as cerebral white matter, between older fallers and non-fallers. In addition, we assessed whether these baseline volumetric differences are associated with changes in cognitive function over 12months. A total of 66 community-dwelling older adults were recruited and categorized by their falls status. Magnetic resonance imaging occurred at baseline and participants' physical and cognitive performances were assessed at baseline and 12-months. At baseline, fallers showed significantly lower volumes in gray matter, subcortical regions, and cerebral white matter compared with non-fallers. Notably, fallers had significantly lower left lateral orbitofrontal white matter volume. Moreover, lower left lateral orbitofrontal white matter volume at baseline was associated with greater decline in set-shifting performance over 12months. Our data suggest that falls may indicate subclinical alterations in regional brain volume that are associated with subsequent decline in executive functions.

The Neurocognitive Basis for Impaired Dual-Task Performance in Senior Fallers.

Falls are a major health-care concern, and while dual-task performance is widely recognized as being impaired in those at-risk for falls, the underlying neurocognitive mechanisms remain unknown. A better understanding of the underlying mechanisms could lead to the refinement and development of behavioral, cognitive, or neuropharmacological interventions for falls prevention. Therefore, we conducted a cross-sectional study with community-dwelling older adults aged 70-80 years with a history of falls (i.e., two or more falls in the past 12 months) or no history of falls (i.e., zero falls in the past 12 months); n = 28 per group. We compared functional activation during cognitive-based dual-task performance between fallers and non-fallers using functional magnetic resonance imaging (fMRI). Executive cognitive functioning was assessed via Stroop, Trail Making, and Digit Span. Mobility was assessed via the Timed Up and Go test (TUG). We found that non-fallers exhibited significantly greater functional activation compared with fallers during dual-task performance in key regions responsible for resolving dual-task interference, including precentral, postcentral, and lingual gyri. Further, we report slower reaction times during dual-task performance in fallers and significant correlations between level of functional activation and independent measures of executive cognitive functioning and mobility. Our study is the first neuroimaging study to examine dual-task performance in fallers, and supports the notion that fallers have reduced functional brain activation compared with non-fallers. Given that dual-task performance-and the underlying neural concomitants-appears to be malleable with relevant training, our study serves as a launching point for promising strategies to reduce falls in the future.

Resistance Training and White Matter Lesion Progression in Older Women: Exploratory Analysis of a 12-Month Randomized Controlled Trial.

OBJECTIVES: To assess whether resistance training (RT) slows the progression of white matter lesions (WMLs) in older women. DESIGN: Secondary analysis of a 52-week randomized controlled trial of RT, the Brain Power Study. SETTING: Community center and research center. PARTICIPANTS: Of 155 community-dwelling women aged 65 to 75 enrolled in the Brain Power Study, 54 who had evidence of WMLs on magnetic resonance imaging (MRI) at baseline were included in this secondary analysis. INTERVENTION: Participants were randomized to once-weekly RT (1× RT), twice-weekly RT (2× RT), or twice-weekly balance and tone (BAT). Assessors were blinded to participant assignments. MEASUREMENTS: WML volume was measured using MRI at baseline and trial completion. RESULTS: At trial completion, the 2× RT group had significantly lower WML volume than the BAT group (P = .03). There was no significant difference between the BAT group and the 1× RT group at trial completion (P = .77). Among participants in the two RT groups, reduced WML progression over 12 months was significantly associated with maintenance of gait speed (correlation coefficient (r) = -0.31, P = .049) but not with executive functions (r = 0.30; P = .06). CONCLUSION: Engaging in progressive RT may reduce WML progression.

Elevated body mass index and maintenance of cognitive function in late life: exploring underlying neural mechanisms.

BACKGROUND: Obesity is associated with vascular risk factors that in turn, may increase dementia risk. However, higher body mass index (BMI) in late life may be neuroprotective. The possible neural mechanisms underlying the benefit of higher BMI on cognition in older adults are largely unknown. Thus, we used functional connectivity magnetic resonance imaging (fcMRI) to examine: (1) the relationship between BMI and functional brain connectivity; and (2) the mediating role of functional brain connectivity in the association between baseline BMI and change in cognitive function over a 12-month period. METHODS: We conducted a 12-month, prospective study among 66 community-dwelling older adults, aged 70 to 80 years, who were categorized as: normal weight (BMI from 18.50 to 24.99); overweight (BMI from 25.00 to 29.99); and obese (BMI ≥ 30.00). At baseline, participants performed a finger-tapping task during fMRI scanning. Relevant neural networks were initially identified through independent component analysis (ICA) and subsequently examined through seed-based functional connectivity analysis. At baseline and 12-months, we measured three executive cognitive processes: (1) response inhibition; (2) set shifting; and (3) working memory. RESULTS: Obese individuals showed lower task-related functional connectivity during finger tapping in the default mode network (DMN) compared with their healthy weight counterparts (p < 0.01). Lower task-related functional connectivity in the DMN at baseline was independently associated with better working memory performance at 12-months (p = 0.02). Finally, DMN functional connectivity during finger tapping significantly mediated the relationship between baseline BMI and working memory at 12-months (indirect effect: -0.155, 95% confidence interval [-0.313, -0.053]). CONCLUSIONS: These findings suggest that functional connectivity of the DMN may be an underlying mechanism by which higher BMI confers protective effects to cognition in late life.

Predicting cognitive function from clinical measures of physical function and health status in older adults.

INTRODUCTION: Current research suggests that the neuropathology of dementia-including brain changes leading to memory impairment and cognitive decline-is evident years before the onset of this disease. Older adults with cognitive decline have reduced functional independence and quality of life, and are at greater risk for developing dementia. Therefore, identifying biomarkers that can be easily assessed within the clinical setting and predict cognitive decline is important. Early recognition of cognitive decline could promote timely implementation of preventive strategies. METHODS: We included 89 community-dwelling adults aged 70 years and older in our study, and collected 32 measures of physical function, health status and cognitive function at baseline. We utilized an L1-L2 regularized regression model (elastic net) to identify which of the 32 baseline measures were strongly predictive of cognitive function after one year. We built three linear regression models: 1) based on baseline cognitive function, 2) based on variables consistently selected in every cross-validation loop, and 3) a full model based on all the 32 variables. Each of these models was carefully tested with nested cross-validation. RESULTS: Our model with the six variables consistently selected in every cross-validation loop had a mean squared prediction error of 7.47. This number was smaller than that of the full model (115.33) and the model with baseline cognitive function (7.98). Our model explained 47% of the variance in cognitive function after one year. DISCUSSION: We built a parsimonious model based on a selected set of six physical function and health status measures strongly predictive of cognitive function after one year. In addition to reducing the complexity of the model without changing the model significantly, our model with the top variables improved the mean prediction error and R-squared. These six physical function and health status measures can be easily implemented in a clinical setting.

Aerobic exercise increases hippocampal volume in older women with probable mild cognitive impairment: a 6-month randomised controlled trial.

BACKGROUND: Mild cognitive impairment (MCI) is a well-recognised risk factor for dementia and represents a vital opportunity for intervening. Exercise is a promising strategy for combating cognitive decline by improving brain structure and function. Specifically, aerobic training (AT) improved spatial memory and hippocampal volume in healthy community-dwelling older adults. In older women with probable MCI, we previously demonstrated that resistance training (RT) and AT improved memory. In this secondary analysis, we investigated: (1) the effect of RT and AT on hippocampal volume and (2) the association between change in hippocampal volume and change in memory. METHODS: 86 women aged 70-80 years with probable MCI were randomly assigned to a 6-month, twice-weekly programme of: (1) AT, (2) RT or (3) balance and tone training (BAT; ie, control). At baseline and trial completion, participants performed a 3T MRI scan to determine hippocampal volume. Verbal memory and learning were assessed by Rey's Auditory Verbal Learning Test. RESULTS: Compared with the BAT group, AT significantly improved left, right and total hippocampal volumes (p≤0.03). After accounting for baseline cognitive function and experimental group, increased left hippocampal volume was independently associated with reduced verbal memory and learning performance as indexed by loss after interference (r=0.42, p=0.03). CONCLUSIONS: Aerobic training significantly increased hippocampal volume in older women with probable MCI. More research is needed to ascertain the relevance of exercise-induced changes in hippocampal volume on memory performance in older adults with MCI. TRAIL REGISTRATION NUMBER: NCT00958867.

Pathways linking regional hyperintensities in the brain and slower gait.

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.

Disruptions in brain networks of older fallers are associated with subsequent cognitive decline: a 12-month prospective exploratory study.

Cognitive impairment and impaired mobility are major public health concerns. There is growing recognition that impaired mobility is an early biomarker of cognitive impairment and dementia. The neural basis for this association is currently unclear. We propose disrupted functional connectivity as a potential mechanism. In this 12-month prospective exploratory study, we compared functional connectivity of four brain networks- the default mode network (DMN), fronto-executive network (FEN), fronto-parietal network (FPN), and the primary motor sensory network (SMN)--between community-dwelling older adults with ≥ two falls in the last 12 months and their non-falling counterparts (≤ one fall in the last 12 months). Functional connectivity was examined both at rest and during a simple motor tapping task. Compared with non-fallers, fallers showed more connectivity between the DMN and FPN during right finger tapping (p  = 0.04), and significantly less functional connectivity between the SMN and FPN during rest (p ≤ 0.05). Less connectivity between the SMN and FPN during rest was significantly associated with greater decline in both cognitive function and mobility over the12-month period (r =  -0.32 and 0.33 respectively; p ≤ 0.04). Thus, a recent history of multiple falls among older adults without a diagnosis of dementia may indicate sub-clinical changes in brain function and increased risk for subsequent decline.

A multistate model of cognitive dynamics in relation to resistance training: the contribution of baseline function.

PURPOSE: We investigated: (1) the effect of different targeted exercise training on an individual's overall probability for cognitive improvement, maintenance, or decline; and (2) the simultaneous effect of targeted exercise training and baseline function on the dynamics of executive functions when a multistate transition model is used. METHODS: Analyses are based on a 12-month randomized clinical trial including 155 community-dwelling women 65-75 years of age who were randomly allocated to once-weekly resistance training (1x RT; n = 54), twice-weekly resistance training (2x RT; n = 52), or twice-weekly balance and tone training (BAT; n = 49). The primary outcome measure was performance on the Stroop test, an executive cognitive test of selective attention and conflict resolution. Secondary outcomes of executive functions were set shifting and working memory. RESULTS: Individuals in the 1x RT or 2x RT group demonstrated a significantly greater probability for improved performance on the Stroop Test (0.49; 95% confidence interval, 0.41-0.57) compared with those in the BAT group (0.25; 95% confidence interval, 0.25-0.40). Resistance training had significant effects on transitions in selective attention and conflict resolution. CONCLUSIONS: Resistance training is efficacious in improving a measure of selective attention and conflict resolution in older women, probably more so among those with greater baseline cognitive function.

Emerging concept: 'central benefit model' of exercise in falls prevention.

Falls are a common geriatric syndrome and are the third leading cause of chonic disability worldwide. Falls are not random events and occur, at least in part, due to impaired physiological function, such as impaired balance, and cognitive impairment. The clinical syndrome of falls is important for Sports and Exercise Medicine Clinicians as there is Level 1 evidence that targeted exercise prescription is an effective intervention strategy. The widely accepted dogma is that improved physical function, balance and muscle strength, underlies the effectiveness of the exercise in reducing falls. However, findings from randomised controlled trials suggest that exercise reduce falls via mechanisms other than improved physiological function. The authors propose that improved cognitive function - specifically, executive functions - and associated functional plasticity may be an important yet underappreciated mechanism by which the exercise reduces falls in older adults.

The association between cognitive function and white matter lesion location in older adults: a systematic review.

BACKGROUND: Maintaining cognitive function is essential for healthy aging and to function autonomously within society. White matter lesions (WMLs) are associated with reduced cognitive function in older adults. However, whether their anatomical location moderates these associations is not well-established. This review systematically evaluates peer-reviewed evidence on the role of anatomical location in the association between WMLs and cognitive function. METHODS: In accordance with the preferred reporting items for systematic reviews and meta-analysis (PRISMA) statement, databases of EMBASE, PUBMED, MEDLINE, and CINAHL, and reference lists of selected papers were searched. We limited our search results to adults aged 60 years and older, and studies published in the English language from 2000 to 2011. Studies that investigated the association between cognitive function and WML location were included. Two independent reviewers extracted: 1) study characteristics including sample size, sample characteristic, and study design; 2) WML outcomes including WML location, WML quantification method (scoring or volume measurement), strength of the MRI magnet in Tesla, and MRI sequence used for WML detection; and 3) cognitive function outcomes including cognitive tests for two cognitive domains of memory and executive function/processing speed. RESULTS: Of the 14 studies included, seven compared the association of subcortical versus periventricular WMLs with cognitive function. Seven other studies investigated the association between WMLs in specific brain regions (e.g., frontal, parietal lobes) and cognitive function. Overall, the results show that a greater number of studies have found an association between periventricular WMLs and executive function/processing speed, than subcortical WMLs. However, whether WMLs in different brain regions have a differential effect on cognitive function remains unclear. CONCLUSIONS: Evidence suggests that periventricular WMLs may have a significant negative impact on cognitive abilities of older adults. This finding may be influenced by study heterogeneity in: 1) MRI sequences, WML quantification methods, and neuropsychological batteries; 2) modifying effect of cardiovascular risk factors; and 3) quality of studies and lack of sample size calculation.