Determinants of exercise adherence in sedentary middle-aged and older adults.

Regular exercise positively impacts neurocognitive health, particularly in aging individuals. However, low adherence, particularly among older adults, hinders the adoption of exercise routines. While brain plasticity mechanisms largely support the cognitive benefits of exercise, the link between physiological and behavioral factors influencing exercise adherence remains unclear. This study aimed to explore this association in sedentary middle-aged and older adults. Thirty-one participants underwent an evaluation of cortico-motor plasticity using transcranial magnetic stimulation (TMS) to measure changes in motor-evoked potentials following intermittent theta-burst stimulation (iTBS). Health history, cardiorespiratory fitness, and exercise-related behavioral factors were also assessed. The participants engaged in a 2-month supervised aerobic exercise program, attending sessions three times a week for 60 min each, totaling 24 sessions at a moderate-to-vigorous intensity. They were divided into Completers (n = 19), who attended all sessions, and Dropouts (n = 12), who withdrew early. Completers exhibited lower smoking rates, exercise barriers, and resting heart rates compared to Dropouts. For Completers, TMS/iTBS cortico-motor plasticity was associated with better exercise adherence (r = -.53, corrected p = .019). Exploratory hypothesis-generating regression analysis suggested that post-iTBS changes (ß = -7.78, p = .013) and self-efficacy (ß = -.51, p = .019) may predict exercise adherence (adjusted-R2 = .44). In conclusion, this study highlights the significance of TMS/iTBS cortico-motor plasticity, self-efficacy, and cardiovascular health in exercise adherence. Given the well-established cognitive benefits of exercise, addressing sedentary behavior and enhancing self-efficacy are crucial for promoting adherence and optimizing brain health. Clinicians and researchers should prioritize assessing these variables to improve the effectiveness of exercise programs.

Clinical classification of memory and cognitive impairment with multimodal digital biomarkers.

INTRODUCTION: Early detection of Alzheimer's disease and cognitive impairment is critical to improving the healthcare trajectories of aging adults, enabling early intervention and potential prevention of decline. METHODS: To evaluate multi-modal feature sets for assessing memory and cognitive impairment, feature selection and subsequent logistic regressions were used to identify the most salient features in classifying Rey Auditory Verbal Learning Test-determined memory impairment. RESULTS: Multimodal models incorporating graphomotor, memory, and speech and voice features provided the stronger classification performance (area under the curve = 0.83; sensitivity = 0.81, specificity = 0.80). Multimodal models were superior to all other single modality and demographics models. DISCUSSION: The current research contributes to the prevailing multimodal profile of those with cognitive impairment, suggesting that it is associated with slower speech with a particular effect on the duration, frequency, and percentage of pauses compared to normal healthy speech.

Digital Clock and Recall is superior to the Mini-Mental State Examination for the detection of mild cognitive impairment and mild dementia.

BACKGROUND: Disease-modifying treatments for Alzheimer's disease highlight the need for early detection of cognitive decline. However, at present, most primary care providers do not perform routine cognitive testing, in part due to a lack of access to practical cognitive assessments, as well as time and resources to administer and interpret the tests. Brief and sensitive digital cognitive assessments, such as the Digital Clock and Recall (DCR™), have the potential to address this need. Here, we examine the advantages of DCR over the Mini-Mental State Examination (MMSE) in detecting mild cognitive impairment (MCI) and mild dementia. METHODS: We studied 706 participants from the multisite Bio-Hermes study (age mean ± SD = 71.5 ± 6.7; 58.9% female; years of education mean ± SD = 15.4 ± 2.7; primary language English), classified as cognitively unimpaired (CU; n = 360), mild cognitive impairment (MCI; n = 234), or probable mild Alzheimer's dementia (pAD; n = 111) based on a review of medical history with selected cognitive and imaging tests. We evaluated cognitive classifications (MCI and early dementia) based on the DCR and the MMSE against cohorts based on the results of the Rey Auditory Verbal Learning Test (RAVLT), the Trail Making Test-Part B (TMT-B), and the Functional Activities Questionnaire (FAQ). We also compared the influence of demographic variables such as race (White vs. Non-White), ethnicity (Hispanic vs. Non-Hispanic), and level of education (≥ 15 years vs. < 15 years) on the DCR and MMSE scores. RESULTS: The DCR was superior on average to the MMSE in classifying mild cognitive impairment and early dementia, AUC = 0.70 for the DCR vs. 0.63 for the MMSE. DCR administration was also significantly faster (completed in less than 3 min regardless of cognitive status and age). Among 104 individuals who were labeled as "cognitively unimpaired" by the MMSE (score ≥ 28) but actually had verbal memory impairment as confirmed by the RAVLT, the DCR identified 84 (80.7%) as impaired. Moreover, the DCR score was significantly less biased by ethnicity than the MMSE, with no significant difference in the DCR score between Hispanic and non-Hispanic individuals. CONCLUSIONS: DCR outperforms the MMSE in detecting and classifying cognitive impairment-in a fraction of the time-while being not influenced by a patient's ethnicity. The results support the utility of DCR as a sensitive and efficient cognitive assessment in primary care settings. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT04733989.

Using digital assessment technology to detect neuropsychological problems in primary care settings.

Introduction: Screening for neurocognitive impairment and psychological distress in ambulatory primary and specialty care medical settings is an increasing necessity. The Core Cognitive Evaluation™ (CCE) is administered/scored using an iPad, requires approximately 8 min, assesses 3- word free recall and clock drawing to command and copy, asks questions about lifestyle and health, and queries for psychological distress. This information is linked with patients' self- reported concerns about memory and their cardiovascular risks. Methods: A total of 199 ambulatory patients were screened with the CCE as part of their routine medical care. The CCE provides several summary indices, and scores on 44 individual digital clock variables across command and copy tests conditions. Results: Subjective memory concerns were endorsed by 41% of participants. Approximately 31% of participants reported psychological distress involving loneliness, anxiety, or depression. Patients with self-reported memory concerns scored lower on a combined delay 3- word/ clock drawing index (p < 0.016), the total summary clock drawing command/ copy score (p < 0.050), and clock drawing to command Drawing Efficiency (p < 0.036) and Simple and Complex Motor (p < 0.029) indices. Patients treated for diabetes and atherosclerotic cardiovascular disease (ASCVD) scored lower on selected CCE outcome measures (p < 0.035). Factor analyses suggest that approximately 10 underlying variables can explain digital clock drawing performance. Discussion: The CCE is a powerful neurocognitive assessment tool that is sensitive to patient's subjective concerns about possible decline in memory, mood symptoms, possible cognitive impairment, and cardiovascular risk. iPad administration ensures total reliability for test administration and scoring. The CCE is easily deployable in outpatient ambulatory primary care settings.

Estimating dementia risk in an African American population using the DCTclock.

The prevalence of Alzheimer's disease (AD) and related dementias (ADRD) is increasing. African Americans are twice as likely to develop dementia than other ethnic populations. Traditional cognitive screening solutions lack the sensitivity to independently identify individuals at risk for cognitive decline. The DCTclock is a 3-min AI-enabled adaptation of the well-established clock drawing test. The DCTclock can estimate dementia risk for both general cognitive impairment and the presence of AD pathology. Here we performed a retrospective analysis to assess the performance of the DCTclock to estimate future conversion to ADRD in African American participants from the Rush Alzheimer's Disease Research Center Minority Aging Research Study (MARS) and African American Clinical Core (AACORE). We assessed baseline DCTclock scores in 646 participants (baseline median age = 78.0 ± 6.4, median years of education = 14.0 ± 3.2, 78% female) and found significantly lower baseline DCTclock scores in those who received a dementia diagnosis within 3 years. We also found that 16.4% of participants with a baseline DCTclock score less than 60 were significantly more likely to develop dementia in 5 years vs. those with the highest DCTclock scores (75-100). This research demonstrates the DCTclock's ability to estimate the 5-year risk of developing dementia in an African American population. Early detection of elevated dementia risk using the DCTclock could provide patients, caregivers, and clinicians opportunities to plan and intervene early to improve cognitive health trajectories. Early detection of dementia risk can also enhance participant selection in clinical trials while reducing screening costs.

Recommending Physical Activity to Your Aging Patients? What Clinicians Need to Know to Increase Adherence From the Older Adult Perspective.

A wealth of scientific evidence supports that being physically active may prevent or delay the onset of cognitive impairment and dementia. However, a critical barrier is that while most clinicians recommend physical activity (PA) and older adults recognize its health benefits, most older adults fail to regularly practice PA. Thus, it is necessary to explore and disseminate knowledge on how to help clinicians truly partner with people and help them to change their behavior and become more active. Clinical and scientific efforts are underway to establish dose-specific PA recommendations for cognitive brain health. However, an important knowledge gap is how to develop effective strategies to increase PA adherence in aging. To better understand the perspective of older adults, we undertook a mixed-method study on sixty-five sedentary older adults at risk for cognitive decline. Participants answered a questionnaire battery related to PA engagement, and a subcohort participated in a remote focus group. Our findings revealed four main themes: First, age and aging are determinants in PA practice. Second, maintaining both an active mind and autonomy are priorities, but planned PA is not usually related as part of being "active." Third, motivational challenges in PA engagement were noted. And fourth, they emphasized a call for tailored recommendations. Therefore, we present a multidimensional model of PA adherence to maximize brain health in older adults and suggest a tool kit and key questions to effectively screen sedentary aging adults and translate current guidelines into the needs of the individual by using behavior change strategies.

Exercise engagement drives changes in cognition and cardiorespiratory fitness after 8 weeks of aerobic training in sedentary aging adults at risk of cognitive decline.

Background: With our aging population, many individuals are at risk of developing age-related cognitive decline. Physical exercise has been demonstrated to enhance cognitive performance in aging adults. This study examined the effects of 8 weeks of aerobic exercise on cognitive performance and cardiorespiratory fitness in sedentary aging adults at risk for cognitive decline. Methods: Fifty-two participants (age 62.9 ± 6.8, 76.9% female) engaged in eight weeks of moderate-to high-intensity exercise (19 in-person, 33 remotely). Global cognition was measured by the Repeatable Battery for the Assessment of Neuropsychological Status, the Delis-Kaplan Executive Function System, and the Digit Span subtest of the Wechsler Adult Intelligence Scale (WAIS) Fourth Edition. Cardiorespiratory fitness was measured via heart rate recovery at minute 1 (HRR1) and 2 (HRR2), and exercise engagement (defined as percent of total exercise time spent in the prescribed heart rate zone). We measured pre and post changes using paired t-tests and mixed effects models, and investigated the association between cardiorespiratory and cognitive performance using multiple regression models. Cohen's d were calculated to estimate effect sizes. Results: Overall, 63.4 % of participants demonstrated high engagement (≥ 70% total exercise time spent in the prescribed heart rate zone). There were significant pre-post improvements in verbal fluency and verbal memory, and a significant decrement in working memory, but these were associated with small effect sizes (Cohen's d <0.5). Concerning cardiorespiratory fitness, there was a pre-to-post significant improvement in HRR1 (p = 0.01, d = 0.30) and HRR2 (p < 0.001, d = 0.50). Multiple regressions revealed significant associations between cardiorespiratory and cognitive performance, but all were associated with small effect sizes (Cohen's d < 0.5). Interestingly, there were significant between-group differences in exercise engagement (all p < 0.001), with remote participants demonstrating greater exercise engagement than in-person participants. Conclusion: Improvements in cognition and cardiorespiratory fitness were observed after 8 weeks of moderate to high-intensity exercise in aging adults. These results suggest that committing to a regular exercise regimen, even for a brief two-month period, can promote improvements in both cardiorespiratory fitness and cognitive performance, and that improvements are driven by exercise engagement.

Exploring the interplay between mechanisms of neuroplasticity and cardiovascular health in aging adults: A multiple linear regression analysis study.

BACKGROUND: Neuroplasticity and cardiovascular health behavior are critically important factors for optimal brain health. OBJECTIVE: To assess the association between the efficacy of the mechanisms of neuroplasticity and metrics of cardiovascular heath in sedentary aging adults. METHODS: We included thirty sedentary individuals (age = 60.6 ± 3.8 y; 63 % female). All underwent assessments of neuroplasticity, measured by the change in amplitude of motor evoked potentials elicited by single-pulse Transcranial Magnetic Stimulation (TMS) at baseline and following intermittent Theta-Burst (iTBS) at regular intervals. Cardiovascular health measures were derived from the Incremental Shuttle Walking Test and included Heart Rate Recovery (HRR) at 1-min/2-min after test cessation. We also collected plasma levels of brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), and c-reactive protein. RESULTS: We revealed moderate but significant relationships between TMS-iTBS neuroplasticity, and the predictors of cardiovascular health (|r| = 0.38 to 0.53, p < .05). HRR1 was the best predictor of neuroplasticity (ß = 0.019, p = .002). The best fit model (Likelihood ratio = 5.83, p = .016) of the association between neuroplasticity and HRR1 (ß = 0.043, p = .002) was selected when controlling for demographics and health status. VEGF and BDNF plasma levels augmented the association between neuroplasticity and HRR1. CONCLUSIONS: Our findings build on existing data demonstrating that TMS may provide insight into neuroplasticity and the role cardiovascular health have on its mechanisms. These implications serve as theoretical framework for future longitudinal and interventional studies aiming to improve cardiovascular and brain health. HRR1 is a potential prognostic measure of cardiovascular health and a surrogate marker of brain health in aging adults.

The Importance of Motivation to Older Adult Physical and Cognitive Exercise Program Development, Initiation, and Adherence.

Brain health is essential to successful aging, and exercise is essential to brain health. Evidence supports the benefits of regular physical and cognitive exercise in preventing or delaying progressin of mild cognitive impairment and dementia. Despite known benefits, motivation to initiate and adhere to an exercise program can be challenging to older adults. We propose that assessment of motivation in the older adult population be part of individualized physical and cognitive exercise program initial development and ongoing precision health coaching to facilitate initiation of-and adherence to-individualized multi-modal exercise programs and sustained exercise engagement. We suggest one published, physical exercise motivation questionnaire and present a new, psychometrically supported, parallel cognitive exercise questionnaire to do so. Needs for-and implications of-continued exercise motivation research using neurophysiologic and neuropsychologic metrics are discussed.

Efficacy of mechanisms of neuroplasticity after a stroke.

BACKGROUND: The sequelae of stoke, including the loss and recovery of function, are strongly linked to the mechanisms of neuroplasticity. Rehabilitation and non-invasive brain stimulation (NIBS) paradigms have shown promise in modulating corticomotor neuroplasticity to promote functional recovery in individuals post-stroke. However, an important limitation to these approaches is that while stroke recovery depends on the mechanisms of neuroplasticity, those mechanisms may themselves be altered by a stroke. OBJECTIVE: Compare Transcranial Magnetic Stimulation (TMS)-based assessments of efficacy of mechanism of neuroplasticity between individuals post-stroke and age-matched controls. METHODS: Thirty-two participants (16 post-stroke, 16 control) underwent an assessment of mechanisms of neuroplasticity, measured by the change in amplitude of motor evoked potentials elicited by single-pulse TMS 10-20 minutes following intermittent theta-burst stimulation (iTBS), and dual-task effect (DTE) reflecting cognitive-motor interference (CMI). In stroke participants, we further collected: time since stroke, stroke type, location, and Stroke Impact Scale 16 (SIS-16). RESULTS: Although there was no between-group difference in the efficacy of TMS-iTBS neuroplasticity mechanism (p = 0.61, η2 = 0.01), the stroke group did not exhibit the expected facilitation to TMS-iTBS (p = 0.60, η2 = 0.04) that was shown in the control group (p = 0.016, η2 = 0.18). Sub-cohort analysis showed a trend toward a difference between those in the late-stage post-stroke and the control group (p = 0.07, η2 = 0.12). Within the post-stroke group, we found significant relationships between TMS-iTBS neuroplasticity and time since stroke onset, physical function (SIS-16), and CMI (all rs > |0.53| and p-values < 0.05). CONCLUSIONS: In this proof-of-principle study, our findings suggested altered mechanisms of neuroplasticity in post-stroke patients which were dependent on time since stroke and related to motor function. TMS-iTBS neuroplasticity assessment and its relationship with clinical functional measures suggest that TMS may be a useful tool to study post-stroke recovery. Due to insufficient statistical power and high variability of the data, generalization of the findings will require replication of the results in a larger, better-characterized cohort.

Associations Between Cognitive Functioning and Mortality in a Population-Based Sample of Older United States Adults: Differences by Sex and Education.

Objective: To determine whether cognition is associated with mortality among older US adults. Methods: We studied 5,989 National Health and Nutrition Examination Survey participants age 60+ in years 1999-2014 with mortality follow-up through 2015. Cognitive function was measured in one standard deviation decrements using the Digit Symbol Substitution Test (DSST), Animal Fluency (AnFl), and two Consortium to Establish a Registry for Alzheimer's Disease (CERAD) tests. Results: Each decrement in cognitive function was associated with increased risk of mortality overall (DSST HR: 1.36, 95% CI: 1.25, 1.48), among women only (AnFl: 1.51, 95% CI: 1.02, 2.24), and among those with less than a high school education only (AnFl HR: 1.46, 95% CI: 1.09, 1.97; CERAD-WL HR: 1.34, 95% CI: 1.07, 1.67; and CERAD-DR HR: 1.38, 95% CI: 1.05, 1.82). Discussion: Among US adults, lower cognitive functioning was associated with mortality; associations were stronger among women and those with less education.

Greater Cognitive-Motor Interference in Individuals Post-Stroke During More Complex Motor Tasks.

BACKGROUND AND PURPOSE: Dual-task (DT) walking assessments allow for the simultaneous evaluation of cognitive and motor performance. During DT walking, individuals may experience interference in one or both tasks, known as cognitive-motor interference (CMI). The primary purpose of this study was to compare CMI between individuals post-stroke and healthy persons group during single- and dual-motor and cognitive tasks, using 2 distinct walking tasks. METHODS: Motor performance was quantified as the total time for the Timed Up and Go (TUG) and gait speed for the 90-second walk (90W). Cognitive performance was measured as the correct response rate (CRR) during serial 7 subtractions. Participants performed the motor and cognitive tasks in isolation for the single-task (ST) and simultaneously for DT conditions, TUG-DT and 90W-DT. A repeated-measures analysis of variance assessed group (poststroke and healthy) by condition (ST and DT) interactions for the TUG, 90W, and CRR. RESULTS: There were significant main effects of group and condition for both the TUG and the 90W (P < 0.05). There was also an interaction effect for the TUG, with individuals post-stroke demonstrating a larger decrement in TUG-DT performance compared with healthy persons (P < 0.05). Furthermore, a significant interaction effect was observed for the CRR, in which healthy individuals exhibited a greater decrement in performance from the ST to the 90W-DT (P < 0.05). DISCUSSION AND CONCLUSIONS: Individuals post-stroke were susceptible to greater motor interference during the more complex motor task, the TUG-DT. However, the only decrements observed in cognitive performance from the ST to DT occurred in healthy individuals during the 90W-DT.Video Abstract available for more insights from the authors (see the Video, Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A367).

Feasibility and Preliminary Efficacy of a Multimodal Approach to Increase Physical Activity in Older Adults With Memory Complaints: The Education for Action Study.

In this randomized controlled pilot trial, the authors explored the feasibility, technology compliance, and preliminary efficacy of the Education for Action (EDU-ACT), a multimodal intervention combining evidence-based strategies of physical activity (PA) education and coaching in PA levels over 4 weeks between EDU-ACT and control groups. The authors also assessed pre-post changes in neurocognitive function, functional mobility and dual-task performance, sleep and quality of life. Thirty-two sedentary older adults with memory complaints (age = 66 ± 5.3) completed the study (EDU-ACT = 18 and control = 14). The EDU-ACT adherence rate was 95%, and compliance of daily PA reporting was, on average, 22.7 days (94.6%). The EDU-ACT group demonstrated a significantly greater number of steps, processing speed, and dual-task performance when compared with controls (p < .05). In this study, a multimodal, evidence-based, low-cost intervention was feasible, well-accepted, with high adherence and compliance rates, and effective at promoting clinically meaningful increases in PA, for at least 1 month postintervention, in older adults with memory complaints.

Aging in the Digital Age: Using Technology to Increase the Reach of the Clinician Expert and Close the Gap Between Health Span and Life Span.

Age-related cognitive impairment (ARCI) has a profound impact on individuals, families, health care systems, and societies at large. Evidence suggests that ARCI is the consequence of underlying brain pathology. Therefore, efforts to minimize the impact of ARCI and thus closing the gap between health span and life span, which has widened in recent years, requires early detection and timely deployment of targeted, personalized interventions. Access to clinical experts is limited and technology screening and assessment methods are thus appealing. However, as traditionally implemented patients were deprived of the benefit of personalized connection with a clinician, which is particularly critical for the prescription and to ensure the adherence to and ultimate success of therapeutic interventions. We present the concept of Intelligent Technology Therapy Assistant (ITA) as a scalable solution that increases the reach of clinical experts while sustaining the personal connection between each patient and their clinician. We illustrate ITA with the "Guttman Neuro Personal Trainer"®, a tele-rehabilitation platform that provides neuropsychological evaluation and care, and the Barcelona Brain Health Initiative (BBHI) multimodal intervention coaching app, a mobile-based platform that provides lifestyle coaching support in domains related to brain health. In addition, we discuss the translation of these models to a large-scale enterprise with Linus Health. To this end, we conclude with a discussion of challenges and opportunities to move the field forward.

Harnessing Neuroplasticity to Promote Brain Health in Aging Adults: Protocol for the MOVE-Cog Intervention Study.

BACKGROUND: Extensive evidence supports a link between aerobic exercise and cognitive improvements in aging adults. A major limitation with existing research is the high variability in cognitive response to exercise. Our incomplete understanding of the mechanisms that influence this variability and the low adherence to exercise are critical knowledge gaps and major barriers for the systematic implementation of exercise for promoting cognitive health in aging. OBJECTIVE: We aimed to provide an in-person and remotely delivered intervention study protocol with the main goal of informing the knowledge gap on the mechanistic action of exercise on the brain by characterizing important mechanisms of neuroplasticity, cardiorespiratory fitness response, and genetics proposed to underlie cognitive response to exercise. METHODS: This is an open-label, 2-month, interventional study protocol in neurologically healthy sedentary adults. This study was delivered fully in-person and in remote options. Participants underwent a total of 30 sessions, including the screening session, 3 pretest (baseline) assessments, 24 moderate-to-vigorous aerobic exercise sessions, and 3 posttest assessments. We recruited participants aged 55 years and above, sedentary, and cognitively healthy. Primary outcomes were neuroplasticity, cognitive function, and cardiorespiratory fitness. Secondary outcomes included genetic factors, endothelium function, functional mobility and postural control, exercise questionnaires, depression, and sleep. We also explored study feasibility, exercise adherence, technology adaptability, and compliance of both in-person and remote protocols. RESULTS: The recruitment phase and data collection of this study have concluded. Results are expected to be published by the end of 2021 or in early 2022. CONCLUSIONS: The data generated in these studies will introduce tangible parameters to guide the development of personalized exercise prescription models for maximal cognitive benefit in aging adults. Successful completion of the specific aims will enable researchers to acquire the appropriate expertise to design and conduct studies by testing personalized exercise interventions in person and remotely delivered, likely to be more effective at promoting cognitive health in aging adults. TRIAL REGISTRATION: ClinicalTrials.gov NCT03804528; http://clinicaltrials.gov/ct2/show/NCT03804528. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR1-10.2196/33589.

Intelligent Coaching Assistant for the Promotion of Healthy Habits in a Multidomain mHealth-Based Intervention for Brain Health.

Brain Health is defined as the development and preservation of optimal brain integrity and neural network functioning for a given age. Recent studies have related healthy habits with better maintenance of brain health across the lifespan. As a part of the Barcelona Brain Health Initiative (BBHI), a mHealth platform has been developed with the purpose of helping people to improve and monitor their healthy habits, facilitating the delivery of health coaching strategies. A decision support system (DSS), named Intelligent Coaching Assistant (ICA), has been developed to ease the work of professional brain health coaches, helping them design and monitor adherence to multidomain interventions in a more efficient manner. Personalized recommendations are based on users' current healthy habits, individual preferences, and motivational aspects. Taking these inputs, an initial user profile is defined, and the ICA applies an algorithm for determining the most suitable personalized intervention plan. An initial validation has been done focusing on assessing the feasibility and usability of the solution, involving 20 participants for three weeks. We conclude that this kind of technology-based intervention is feasible and implementable in real-world settings. Importantly, the personalized intervention proposal generated by the DSS is feasible and its acceptability and usability are high.

Associations Between Cardiorespiratory Fitness, Cardiovascular Risk, and Cognition Are Mediated by Structural Brain Health in Midlife.

Background Evidence in older adults suggests that higher cardiorespiratory fitness and lower cardiovascular risk are associated with greater cognition. However, given that changes in the brain that lead to cognitive decline begin decades before the onset of symptoms, understanding the mechanisms by which modifiable cardiovascular factors are associated with brain health in midlife is critical and can lead to the development of strategies to promote and maintain brain health as we age. Methods and Results In 501 middle-aged (aged 40-65 years) adult participants of the BBHI (Barcelona Brain Health Initiative), we found differential associations among cardiorespiratory fitness, cardiovascular risk, and cognition and cortical thickness. Higher cardiorespiratory fitness was significantly associated with better visuospatial abilities and frontal loading abstract problem solving (ß=3.16, P=0.049) in the older middle-aged group (aged 55-65 years). In contrast, cardiovascular risk was negatively associated with better visuospatial reasoning and problem-solving abilities (ß=-0.046, P=0.002), flexibility (ß=-0.054, P<0.001), processing speed (ß=-0.115, P<0.001), and memory (ß=-0.120, P<0.001). Cortical thickness in frontal regions mediated the relationship between cardiorespiratory fitness and cognition, whereas cortical thickness in a disperse network spanning multiple cortical regions across both hemispheres mediated the relationship between cardiovascular risk and cognition. Conclusions The relationships between modifiable cardiovascular factors, cardiorespiratory fitness, and cardiovascular risk, and cognition are present in healthy middle-aged adults. These relationships are also mediated by brain structure highlighting a potential mechanistic pathway through which higher cardiorespiratory fitness and lower cardiovascular risk can positively impact cognitive function in midlife.

Large-scale analysis of interindividual variability in single and paired-pulse TMS data.

OBJECTIVE: This study brought together over 60 transcranial magnetic stimulation (TMS) researchers to create the largest known sample of individual participant single and paired-pulse TMS data to date, enabling a more comprehensive evaluation of factors driving response variability. METHODS: Authors of previously published studies were contacted and asked to share deidentified individual TMS data. Mixed-effects regression investigated a range of individual and study level variables for their contribution to variability in response to single and paired-pulse TMS data. RESULTS: 687 healthy participant's data were pooled across 35 studies. Target muscle, pulse waveform, neuronavigation use, and TMS machine significantly predicted an individual's single-pulse TMS amplitude. Baseline motor evoked potential amplitude, motor cortex hemisphere, and motor threshold (MT) significantly predicted short-interval intracortical inhibition response. Baseline motor evoked potential amplitude, test stimulus intensity, interstimulus interval, and MT significantly predicted intracortical facilitation response. Age, hemisphere, and TMS machine significantly predicted MT. CONCLUSIONS: This large-scale analysis has identified a number of factors influencing participants' responses to single and paired-pulse TMS. We provide specific recommendations to minimise interindividual variability in single and paired-pulse TMS data. SIGNIFICANCE: This study has used large-scale analyses to give clarity to factors driving variance in TMS data. We hope that this ongoing collaborative approach will increase standardisation of methods and thus the utility of single and paired-pulse TMS.

Large-scale analysis of interindividual variability in theta-burst stimulation data: Results from the 'Big TMS Data Collaboration'.

BACKGROUND: Many studies have attempted to identify the sources of interindividual variability in response to theta-burst stimulation (TBS). However, these studies have been limited by small sample sizes, leading to conflicting results. OBJECTIVE/HYPOTHESIS: This study brought together over 60 TMS researchers to form the 'Big TMS Data Collaboration', and create the largest known sample of individual participant TBS data to date. The goal was to enable a more comprehensive evaluation of factors driving TBS response variability. METHODS: 118 corresponding authors of TMS studies were emailed and asked to provide deidentified individual TMS data. Mixed-effects regression investigated a range of individual and study level variables for their contribution to iTBS and cTBS response variability. RESULTS: 430 healthy participants' TBS data was pooled across 22 studies (mean age = 41.9; range = 17-82; females = 217). Baseline MEP amplitude, age, target muscle, and time of day significantly predicted iTBS-induced plasticity. Baseline MEP amplitude and timepoint after TBS significantly predicted cTBS-induced plasticity. CONCLUSIONS: This is the largest known study of interindividual variability in TBS. Our findings indicate that a significant portion of variability can be attributed to the methods used to measure the modulatory effects of TBS. We provide specific methodological recommendations in order to control and mitigate these sources of variability.