The Effect of Computerized Cognitive Training, with and without Exercise, on Cortical Volume and Thickness and Its Association with Gait Speed in Older Adults: A Secondary Analysis of a Randomized Controlled Trial.

Background: Slower walking is associated with changes in cortical volume and thickness. Computerized cognitive training (CCT) and exercise improve cortical volume and thickness and thus, may promote gait speed. Slowing of gait is predictive of Alzheimer's disease. Objective: To examine: 1) the effect of CCT, with or without physical exercise, on cortical volume and thickness and; 2) the association of changes in cortical volume and thickness with changes in gait speed. Methods: A subset of 124 adults (n = 53), aged 65-85 years, enrolled in an 8-week randomized controlled trial and completed T1-weighted MRI and 4-meter walk at baseline and 8 weeks. Participants were randomized to: 1) active control (BAT; n = 19); 2) CCT (n = 17); or 3) CCT preceded by exercise (Ex-CCT; n = 17). Change in cortical volume and thickness were assessed and compared across all groups using Freesurfer. RESULTS: BAT versus CCT increased left rostral middle frontal gyrus volume (p  = 0.027) and superior temporal gyrus thickness (p = 0.039). Ex-CCT versus CCT increased left cuneus thickness (p < 0.001) and right post central gyrus thickness (p = 0.005), and volume (p < 0.001). Ex-CCT versus BAT increased left (p = 0.001) and right (p = 0.020) superior parietal gyri thickness. There were no significant between-group differences in gait speed (p > 0.175). Increased left superior parietal volume (p = 0.036, r = 0.340) and thickness (p = 0.002, r = 0.348), right post central volume (p = .017, r = 0.341) and thickness (p = 0.001, r = 0.348), left banks of superior temporal sulcus thickness (p = 0.002, r = 0.356), and left precuneus thickness (p < 0.001, r = 0.346) were associated with increased gait speed. CONCLUSIONS: CCT with physical exercise, but not CCT alone, improves cortical volume and thickness in older adults. These changes may contribute to the maintenance of gait speed in aging.

Improved intraindividual variability in cognitive performance following cognitive and exercise training in older adults.

OBJECTIVE: Increased intraindividual variability (IIV) of cognitive performance is a marker of cognitive decline in older adults. Whether computerized cognitive training (CCT) and aerobic exercise counteracts cognitive decline by reducing IIV is unknown. We investigated the effects of CCT with or without aerobic exercise on IIV in older adults. METHODS: This was a secondary analysis of an 8-week randomized controlled trial. Older adults (aged 65-85 years) were randomized to CCT alone (n = 41), CCT with aerobic exercise (n = 41), or an active control group (n = 42). The CCT group trained using the Fit Brains® platform 3×/week for 1 hr (plus 3×/week of home-based training). The CCT with aerobic exercise group received 15 min of walking plus 45 min of Fit Brains® 3×/week (plus 3×/week of home-based training). The control group received sham exercise and cognitive training (3×/week for 1 hr). We computed reaction time IIV from the Dimensional Change Card Sort Test, Flanker Inhibitory Control and Attention Test (Flanker), and Pattern Comparison Processing Speed Test (PACPS). RESULTS: Compared with the control group, IIV reduced in a processing speed task (PACPS) following CCT alone (mean difference [95% confidence interval]: -0.144 [-0.255 to -0.034], p < 0.01) and CCT with aerobic exercise (-0.113 [-0.225 to -0.001], p < 0.05). Attention (Flanker congruent) IIV was reduced only after CCT with aerobic exercise (-0.130 [-0.242 to -0.017], p < 0.05). CONCLUSIONS: A CCT program promoted cognitive health via reductions in IIV of cognitive performance and combining it with aerobic exercise may result in broader benefits.

Aerobic exercise training effects on hippocampal volume in healthy older individuals: a meta-analysis of randomized controlled trials.

We conducted a meta-analysis of randomized controlled trials investigating the effects of aerobic exercise training (AET) lasting ≥ 4 weeks on hippocampal volume and cardiorespiratory fitness (CRF) in cognitively unimpaired, healthy older individuals. Random-effects robust variance estimation models were used to test differences between AET and controls, while meta-regressions tested associations between CRF and hippocampal volume changes. We included eight studies (N = 554) delivering fully supervised AET for 3 to 12 months (M = 7.8, SD = 4.5) with an average AET volume of 129.85 min/week (SD = 45.5) at moderate-to-vigorous intensity. There were no significant effects of AET on hippocampal volume (SMD = 0.10, 95% CI - 0.01 to 0.21, p = 0.073), but AET moderately improved CRF (SMD = 0.30, 95% CI 0.12 to 0.48, p = 0.005). Improvement in CRF was not associated with changes in hippocampal volume (bSE = 0.05, SE = 0.51, p = 0.923). From the limited number of studies, AET does not seem to impact hippocampal volume in cognitively unimpaired, healthy older individuals. Notable methodological limitations across investigations might mask the lack of effects.

Reshaping the path of mild cognitive impairment by refining exercise prescription: a study protocol of a randomized controlled trial to understand the "what," "for whom," and "how" of exercise to promote cognitive function.

BACKGROUND: Targeted exercise training is a promising strategy for promoting cognitive function and preventing dementia in older age. Despite the utility of exercise as an intervention, variation still exists in exercise-induced cognitive gains and questions remain regarding the type of training (i.e., what), as well as moderators (i.e., for whom) and mechanisms (i.e., how) of benefit. Both aerobic training (AT) and resistance training (RT) enhance cognitive function in older adults without cognitive impairment; however, the vast majority of trials have focused exclusively on AT. Thus, more research is needed on RT, as well as on the combination of AT and RT, in older adults with mild cognitive impairment (MCI), a prodromal stage of dementia. Therefore, we aim to conduct a 6-month, 2 × 2 factorial randomized controlled trial in older adults with MCI to assess the individual effects of AT and RT, and the combined effect of AT and RT on cognitive function and to determine the possible underlying biological mechanisms. METHODS: Two hundred and sixteen community-dwelling adults, aged 65 to 85 years, with MCI from metropolitan Vancouver will be recruited to participate in this study. Randomization will be stratified by biological sex and participants will be randomly allocated to one of the four experimental groups: (1) 4×/week balance and tone (BAT; i.e., active control); (2) combined 2×/week AT + 2×/week RT; (3) 2×/week AT + 2×/week BAT; or (4) 2×/week RT + 2×/week BAT. The primary outcome is cognitive function as measured by the Alzheimer's Disease Assessment Scale-Cognitive-Plus. Secondary outcomes include cognitive function, health-related quality of life, physical function, actigraphy measures, questionnaires, and falls. Outcomes will be measured at baseline, 6 months (i.e., trial completion), and 18 months (i.e., 12-month follow-up). DISCUSSION: Establishing the efficacy of different types and combinations of exercise training to minimize cognitive decline will advance our ability to prescribe exercise as "medicine" to treat MCI and delay the onset and progression of dementia. This trial is extremely timely as cognitive impairment and dementia pose a growing threat to global public health. TRIAL REGISTRATION: ClinicalTrials.gov NCT02737878 . Registered on April 14, 2016.

Objective Sleep Quality and the Underlying Functional Neural Correlates Among Older Adults with Possible Mild Cognitive Impairment.

BACKGROUND: Poor sleep quality is common among older individuals with mild cognitive impairment (MCI) and may be a consequence of functional alterations in the brain; yet few studies have investigated the underlying neural correlates of actigraphy-measured sleep quality in this cohort. OBJECTIVE: The objective of this study was to examine the relationship between brain networks and sleep quality measured by actigraphy. METHODS: In this cross-sectional analysis, sleep efficiency and sleep fragmentation were estimated using Motionwatch8 (MW8) over a period of 14 days in 36 community-dwelling older adults with possible MCI aged 65-85 years. All 36 participants underwent resting-state functional magnetic resonance imaging (fMRI) scanning. Independent associations between network connectivity and MW8 measures of sleep quality were determined using general linear modeling via FSL. Networks examined included the somatosensory network (SMN), frontoparietal network (FPN), and default mode network (DMN). RESULTS: Across the 36 participants (mean age 71.8 years; SD = 5.2 years), mean Montreal Cognitive Assessment score was 22.5 (SD = 2.7) and Mini-Mental State Examination score was 28.3 (SD = 1.5). Mean sleep efficiency and fragmentation index was 80.1% (SD = 10.0) and 31.8 (SD = 10.4) respectively. Higher sleep fragmentation was significantly correlated with increased connectivity between the SMN and insula, the SMN and posterior cingulate, as well as FPN and primary motor area (FDR-corrected, p < 0.004). CONCLUSION: Functional connectivity between brain regions involved in attentional and somatosensory processes may be associated with disrupted sleep in older adults with MCI.

Reshaping the path of vascular cognitive impairment with resistance training: a study protocol for a randomized controlled trial.

BACKGROUND: Subcortical ischemic vascular cognitive impairment (SIVCI) is the most common form of vascular cognitive impairment. Importantly, SIVCI is considered the most treatable form of cognitive impairment in older adults, due to its modifiable risk factors such as hypertension, diabetes mellitus, and hypercholesterolemia. Exercise training is a promising intervention to delay the progression of SIVCI, as it actively targets these cardiometabolic risk factors. Despite the demonstrated benefits of resistance training on cognitive function and emerging evidence suggesting resistance training may reduce the progression of white matter hyperintensities (WMHs), research on SIVCI has predominantly focused on the use of aerobic exercise. Thus, the primary aim of this proof-of-concept randomized controlled trial is to investigate the efficacy of a 12-month, twice-weekly progressive resistance training program on cognitive function and WMH progression in adults with SIVCI. We will also assess the efficiency of the intervention. METHODS: Eighty-eight community-dwelling adults, aged > 55 years, with SIVCI from metropolitan Vancouver will be recruited to participate in this study. SIVCI will be determined by the presence of cognitive impairment (Montreal Cognitive Assessment < 26) and cerebral small vessel disease using computed tomography or magnetic resonance imaging. Participants will be randomly allocated to a twice-weekly exercise program of (1) progressive resistance training or (2) balance and tone training (i.e., active control). The primary outcomes are cognitive function measured by the Alzheimer's Disease Assessment Scale-Cognitive-Plus (ADAS-Cog-13 with additional cognitive tests) and WMH progression. DISCUSSION: The burden of SIVCI is immense, and to our knowledge, this will be the first study to quantify the effect of progressive resistance training on cognitive function and WMH progression among adults with SIVCI. Slowing the rate of cognitive decline and WMH progression could preserve functional independence and quality of life. This could lead to reduced health care costs and avoidance of early institutional care. TRIAL REGISTRATION: ClinicalTrials.gov NCT02669394 . Registered on February 1, 2016.

Functional Connectivity and Response Inhibition: A Secondary Analysis of an 8-Week Randomized Controlled Trial of Computerized Cognitive Training.

BACKGROUND: Evidence suggests that computerized cognitive training (CCT) can improve cognitive function in older adults, particularly executive functions. However, the underlying mechanisms by which CCT may improve executive functions are not well established. OBJECTIVE: To determine: 1) inter-network functional connectivity correlates of changes in executive functions; and 2) the effect of CCT on these functional connectivity correlates. METHODS: This secondary analysis included a subset of 124 adults aged 65-85 years enrolled in an 8-week randomized controlled trial of CCT. Participants were randomized to either: 1) group-based CCT 3x/week for 1 hour plus 3x/week home-based training; 2) group-based CCT preceded by brisk walking (Ex+CCT) 3x/week for 1 hour plus 3x/week home-based training; or 3) group-based balanced and toned (BAT) classes 3x/week for 1 hour (control). At baseline and trial completion, 65 of the 124 participants completed resting-state functional magnetic resonance imaging and neuropsychological tests of executive functions, specifically the Stroop Colour-Word Test and Flanker Test. RESULTS: Improved performance on the Stroop Colour-Word Test and Flanker Test were associated with decreased correlation between the default mode network (DMN) and the fronto-parietal network (FPN) (p < 0.05). Compared with BAT, CCT alone significantly decreased correlation between the left dorsolateral prefrontal cortex and both the left and right medial temporal gyrus (-0.143, 95%CI [-0.256,-0.030], p = 0.014, and -0.123, 95%CI [-0.242,-0.004], p = 0.043, respectively). CONCLUSION: Decreased correlation between DMN and FPN, indicating less connection between these networks, may be an underlying mechanism by which CCT improves executive functions. Future studies are needed to replicate this finding.

Exploring the Contribution of Myelin Content in Normal Appearing White Matter to Cognitive Outcomes in Cerebral Small Vessel Disease.

BACKGROUND: Myelin damage is a salient feature in cerebral small vessel disease (cSVD). Of note, myelin damage extends into the normal appearing white matter (NAWM). Currently, the specific role of myelin content in cognition is poorly understood. OBJECTIVE: The objective of this exploratory study was to investigate the association between NAWM myelin and cognitive function in older adults with cSVD. METHODS: This exploratory study included 55 participants with cSVD. NAWM myelin was measured using myelin water imaging and was quantified as myelin water fraction (MWF). Assessment of cognitive function included processing speed (Trail Making Test Part A), set shifting (Trail Making Test Part B minus A), working memory (Verbal Digit Span Backwards Test), and inhibition (Stroop Test). Multiple linear regression analyses assessed the contribution of NAWM MWF on cognitive outcomes controlling for age, education, and total white matter hyperintensity volume. The overall alpha was set at ≤0.05. RESULTS: After accounting for age, education, and total white matter hyperintensity volume, lower NAWM MWF was significantly associated with slower processing speed (ß â€Š= -0.29, p = 0.037) and poorer working memory (ß= 0.30, p = 0.048). NAWM MWF was not significantly associated with set shifting or inhibitory control (p > 0.132). CONCLUSION: Myelin loss in NAWM may play a role in the evolution of impaired processing speed and working memory in people with cSVD. Future studies, with a longitudinal design and larger sample sizes, are needed to fully elucidate the role of myelin as a potential biomarker for cognitive function.

The Effects of Computerized Cognitive Training With and Without Physical Exercise on Cognitive Function in Older Adults: An 8-Week Randomized Controlled Trial.

BACKGROUND: Aging is characterized by cognitive changes in specific domains, such as declines in memory and executive functions. Given the world's aging population, it is important to identify and evaluate strategies that promote healthy cognitive aging. Besides exercise, computerized cognitive training (CCT) is a promising approach to promote cognitive function. Moreover, a single bout of exercise immediately prior to CCT may provide additional cognitive benefits. METHODS: An 8-week proof-of-concept randomized controlled trial to investigate the effect of a commercial CCT intervention, alone and when preceded by exercise, on cognitive function. Participants (124; aged 65-85 years) performed 8 weeks of: (i) Group-based CCT (Fit Brains) 3×/week for 1 hour plus 3×/week home-based training; (ii) Group-based CCT preceded by exercise (Ex-CCT) 3×/week for 1 hour plus 3×/week home-based training (exercise+CCT); or (iii) Group-based balanced and toned (BAT) classes 3×/week for 1 hour (control). Memory was assessed by the Rey Auditory Verbal Learning Test. Executive functions were assessed using the: (i) Stroop Test, (ii) Trail Making Tests (TMT), (iii) Flanker Test, and (iv) Dimensional Change Card Sort Test (DCCS). RESULTS: At trial completion, there were no significant between-group differences in memory (p > .05). However, compared with BAT, CCT, and Ex-CCT significantly improved Stroop performance (-10.72, 95% confidence interval [CI]: -16.53, -4.91; -7.95, 95% CI: -13.77, -2.13, respectively). Moreover, Ex-CCT significantly improved the performance on TMT (-13.65, 95% CI: -26.09, -1.22), the Flanker Test (6.72, 95% CI: 2.55, 10.88), and the DCCS Test (6.75, 95% CI: 0.99, 12.50). CONCLUSION: An 8-week CCT program may promote executive functions in older adults and combining it with a bout of exercise may provide broader benefits.

Biological Sex: A Potential Moderator of Physical Activity Efficacy on Brain Health.

The number of older people worldwide living with cognitive impairment and neurodegenerative diseases is growing at an unprecedented rate. Despite accumulating evidence that engaging in physical activity is a promising primary behavioral strategy to delay or avert the deleterious effects of aging on brain health, a large degree of variation exists in study findings. Thus, before physical activity and exercise can be prescribed as "medicine" for promoting brain health, it is imperative to understand how different biological factors can attenuate or amplify the effects of physical activity on cognition at the individual level. In this review article, we briefly discuss the current state of the literature, examining the relationship between physical activity and brain health in older adults and we present the argument that biological sex is a potent moderator of this relationship. Additionally, we highlight some of the potential neurobiological mechanisms underlying this sex difference for this relatively new and rapidly expanding line of research.

The effects of an 8-week computerized cognitive training program in older adults: a study protocol for a randomized controlled trial.

BACKGROUND: Given the world's aging population, it is important to identify strategies that promote healthy cognitive aging and minimize cognitive decline. Currently, no curative pharmaceutical therapy exists for cognitive impairment and dementia. As a result, there is much interest in lifestyle approaches. Specifically, complex mental activity, such as cognitive training, may be a promising method to combat cognitive decline in older adults. As such, the industry of commercial computerized cognitive training (CCT) applications has rapidly grown in the last decade. However, the efficacy of these commercial products is largely not established. Moreover, exercise is a recognized strategy for promoting cognitive outcomes in older adults and may augment the efficacy of computerized cognitive training applications. Therefore, we propose a proof-of-concept randomized controlled trial (RCT) to examine the effect of a commercial CCT program in community-dwelling older adults. METHODS: An 8-week RCT to examine the effect of a commercial CCT program, alone and preceded by a 15-min brisk walk, on cognitive function and explore the underlying neural mechanisms in adults aged 65-85 years old. Participants will be randomized to one of three intervention groups: 1) Computerized cognitive training (FBT); 2) A 15-min brisk walk followed by computerized cognitive training (Ex-FBT); or 3) A combination of educational classes, sham cognitive training, and balanced and tone exercises (active control, BAT). Participants in all intervention groups will attend three one-hour classes per week over the course of the intervention. Participants will be assessed at baseline, trial completion, and 1-year post study completion (1-year follow-up). DISCUSSION: If results from this study show benefits for cognition at trial completion, CCT programs, alone or in combination with walking, might be a strategy to promote healthy cognitive aging in older adults. In addition, results from the 1-year follow-up measurement could provide important information regarding the long-term benefits of these CCT programs. TRIAL REGISTRATION: ClinicalTrials.gov Protocol Registration System: NCT02564809; registered September 1, 2015.

Effects of computerized cognitive training on neuroimaging outcomes in older adults: a systematic review.

BACKGROUND: Worldwide, the population is aging and the number of individuals diagnosed with dementia is rising rapidly. Currently, there are no effective pharmaceutical cures. Hence, identifying lifestyle approaches that may prevent, delay, or treat cognitive impairment and dementia in older adults is becoming increasingly important. Computerized Cognitive Training (CCT) is a promising strategy to combat cognitive decline. Yet, the underlying mechanisms of the effect of CCT on cognition remain poorly understood. Hence, the primary objective of this systematic review was to examine peer-reviewed literature ascertaining the effect of CCT on both structural and functional neuroimaging measures among older adults to gain insight into the underlying mechanisms by which CCT may benefit cognitive function. METHODS: In accordance with PRISMA guidelines, we used the following databases: MEDLINE, EMBASE, and CINAHL. Two independent reviewers abstracted data using pre-defined terms. These included: main study characteristics such as the type of training (i.e., single- versus multi-domain), participant demographics (age ≥ 50 years; no psychiatric conditions), and the inclusion of neuroimaging outcomes. The Physiotherapy Evidence Database (PEDro) scale was used to assess quality of all studies included in this systematic review. RESULTS: Nine studies were included in this systematic review, with four studies including multiple MRI sequences. Results of this systematic review are mixed: CCT was found to increase and decrease both brain structure and function in older adults. In addition, depending on region of interest, both increases and decreases in structure and function were associated with behavioural performance. CONCLUSIONS: Of all studies included in this systematic review, results from the highest quality studies, which were two randomized controlled trials, demonstrated that multi-domain CCT could lead to increases in hippocampal functional connectivity. Further high quality studies that include an active control, a sample size calculation, and an appropriate training dosage, are needed to confirm these findings and their relation to cognition.

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.