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Home / Brain Training Exercises for Patients With Early Signs of Dementia/alzhe Reviewimers Reviews

Brain Training Exercises for Patients With Early Signs of Dementia/alzhe Reviewimers Reviews

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Open Access

Peer-reviewed

Research Article

Aerobic exercise for Alzheimer's illness: A randomized controlled pilot trial

  • Jill Grand. Morris,
  • Eric D. Vidoni,
  • David K. Johnson,
  • Angela Van Sciver,
  • Jonathan D. Mahnken,
  • Robyn A. Honea,
  • Heather M. Wilkins,
  • William M. Brooks,
  • Sandra A. Billinger,
  • Russell H. Swerdlow

PLOS

x

  • Published: February 10, 2017
  • https://doi.org/10.1371/periodical.pone.0170547

Abstract

Groundwork

There is increasing interest in the role of concrete exercise as a therapeutic strategy for individuals with Alzheimer'southward affliction (AD). Nosotros assessed the effect of 26 weeks (vi months) of a supervised aerobic exercise program on memory, executive function, functional power and depression in early Advertising.

Methods and findings

This report was a 26-week randomized controlled trial comparison the effects of 150 minutes per calendar week of aerobic exercise vs. not-aerobic stretching and toning command intervention in individuals with early on Advertizing. A total of 76 well-characterized older adults with likely Advert (mean age 72.ix [7.7]) were enrolled and 68 participants completed the study. Exercise was conducted with supervision and monitoring past trained exercise specialists. Neuropsychological tests and surveys were conducted at baseline,13, and 26 weeks to assess memory and executive function composite scores, functional ability (Disability Assessment for Dementia), and depressive symptoms (Cornell Calibration for Low in Dementia). Cardiorespiratory fettle testing and encephalon MRI was performed at baseline and 26 weeks. Aerobic exercise was associated with a small gain in functional ability (Inability Assessment for Dementia) compared to individuals in the ST group (X2 = 8.2, p = 0.02). In that location was no clear upshot of intervention on other primary outcome measures of Memory, Executive Office, or depressive symptoms. Nevertheless, secondary analyses revealed that modify in cardiorespiratory fettle was positively correlated with alter in memory functioning and bilateral hippocampal volume.

Conclusions

Aerobic exercise in early Advertisement is associated with benefits in functional ability. Exercise-related gains in cardiorespiratory fitness were associated with improved retentiveness performance and reduced hippocampal atrophy, suggesting cardiorespiratory fitness gains may be important in driving encephalon benefits.

Citation: Morris JK, Vidoni ED, Johnson DK, Van Sciver A, Mahnken JD, Honea RA, et al. (2017) Aerobic exercise for Alzheimer's disease: A randomized controlled pilot trial. PLoS One 12(2): e0170547. https://doi.org/10.1371/periodical.pone.0170547

Editor: Andrew Scholey, Swinburne Academy, Commonwealth of australia

Received: August 25, 2016; Accustomed: January v, 2017; Published: Feb ten, 2017

Copyright: © 2017 Morris et al. This is an open up access article distributed under the terms of the Creative Eatables Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: The data are available from the Harvard Dataverse (doi:10.7910/DVN/ER8ICT).

Funding: Research reported in this publication was supported past the National Institutes of Health under award numbers R01 AG033673, F32 AG044953, K99 AG050490, P30 AG035982, S10 RR29577, UL1 TR000001, KL2 TR000119, K01 AG035042, and K01 HD067318. Additional support was provided by the Foundation for Concrete Therapy New Investigator Fellowship Training Initiative and the Hyndman Foundation. The Hoglund Brain Imaging Center is supported by a generous souvenir from Forrest and Sally Hoglund. The content is solely the responsibleness of the authors and does not necessarily represent the official views of the funders.

Competing interests: The authors have declared that no competing interests exist.

Introduction

An estimated five.3 meg Americans have Alzheimer'southward disease (Advertizing) and the prevalence is expected to double by mid-century.[one] At that place are currently no affliction-modifying or preventive treatments for AD.[ii] However, animate being enquiry suggests that exercise positively impacts encephalon health through neurotrophic, neurogenic and vascular mechanisms.[three–8] Limited but compelling data suggests that do may decrease neuropathological brunt[9] and increment hippocampal neurogenesis.[10]

Observational prove in humans suggests college levels of cardiorespiratory fitness and physical activity are associated with greater brain volume, less brain cloudburst, slower dementia progression and reduced risk of dementia.[11–17] Increased cardiorespiratory fettle also attenuates the detrimental effects of cognitive amyloid on cognition.[eighteen] Randomized controlled trials of aerobic do (AEx) in individuals with mild cognitive impairment (MCI)[xix] and subjective memory complaints[xx] have found practise improved cerebral office. A split up dwelling house-based plan of exercise and counseling benefited concrete function and depression compared to usual intendance in persons with Ad.[21] Another report of people with MCI showed some cognitive test score improvement when analyses were restricted to compliant exercisers.[22] Although current show remains insufficient to conclude that practise is an effective therapeutic for AD or cognitive refuse,[2, 23] practice continues to exist a promising area of inquiry for Advertizement handling.[24] Aerobic exercise offers a low-price, low-chance, widely-available intervention that may take disease modifying effects. Demonstrating that aerobic do alters the Advert procedure would accept enormous public wellness implications.

Our objective for this pilot report was to constitute preliminary efficacy for a community-based, structured aerobic exercise intervention that meets standard public health guidelines (~ 150 minutes / calendar week of moderate intensity aerobic practise). We hypothesized that cognition, functional ability, and depression would benefit from aerobic exercise compared to non-aerobic stretching and toning exercises in a well-characterized sample of individuals with Advertising-related cognitive impairment. We too hypothesized that these benefits would exist proportional to cardiorespiratory fitness gain.

Methods

The Alzheimer's Affliction Exercise Program Trial (Proficient: ClinicalTrials.gov, NCT01128361) was designed as a pilot randomized controlled trial of 26 weeks of aerobic exercise (AEx) versus a non-aerobic stretching and toning control plan (ST). The study included adults over 55 in the primeval stages of Advertising-related cerebral decline. Participants were assigned to AEx and ST groups in a 1:i ratio. We recruited participants from August 2, 2010 through September 26, 2014. Follow-upwardly testing was completed by April 17, 2015. Details of the written report protocol have been previously published.[25] All testing was performed at the University of Kansas Medical Center. The intervention was administered at sixteen YMCA of Greater Kansas Metropolis facilities.

Participants

Participants were recruited as a convenience sample of volunteers through print ad, community talks, memory clinic referral and existing research participant databases. The University of Kansas Alzheimer's Disease Center (KU ADC) and the YMCA jointly designed and distributed these materials. YMCA membership and certified personal trainer fees were covered past the study. Inclusion criteria included MCI or dementia with etiologic diagnosis of probable Advertisement based on clinical and cognitive examination results using standard criteria;[26, 27] Clinical Dementia Rating (CDR) of 0.5 or i (very mild to mild dementia);[28] at least 55 years of age; sedentary or underactive as defined past the Telephone Cess of Concrete Activity;[29] community dwelling with a supportive caregiver willing to back-trail participants to visits as necessary; adequate visual and auditory ability to perform cerebral testing; stable medication dose (thirty days); and ability to participate in all scheduled evaluations and the practise program. Exclusion criteria included clinically meaning psychiatric disorder; systemic illness or infection likely to affect safety; clinically-axiomatic stroke; myocardial infarction or coronary artery disease in the terminal ii years; uncontrolled hypertension in the last 6 months; cancer in the final 5 years; drug or alcohol abuse in the last 2 years; insulin dependent diabetes; or significant pain or musculoskeletal symptoms that would prohibit exercise.

Interested individuals completed a telephone screen of medical history followed by in-person screening of those who remained interested and appeared eligible. All participants and a report partner/caregiver provided institutionally approved, written, informed consent nether a study protocol (#11969) approved by the KU Medical Center Institutional Review Board, which likewise acted as the compliance entity for the YMCA. The screening evaluation included a thorough clinical exam including CDR.[28]

Sample size, randomization, blinding and safety

Participants were block randomized, stratified by age (split at 75) and sex, to balance treatment arms. Our enrollment goal of 80 was determined to provide estimates of intervention effect sizes likewise equally preliminary hypothesis testing with the recognition that this pocket-size pilot written report would non be definitive. We reviewed the exercise intervention literature, which has widely varying effect estimates from a diverse participant population with relatively few trials specifically for individuals with cognitive damage. We thus selected a sample size with twenty% expected attrition that would yield l% ability to observe an issue in our primary cognitive outcomes. Additional detail regarding the sample size calculation, including the hypothesis tested, parameters used, and allowances fabricated for refusals and losses to follow-up can exist found in our published protocol.[25] I investigator (JDM) constructed the allotment schedule using SAS, placing alphabetize cards in 320 sequentially numbered, sealed envelopes grouped by historic period and sexual activity strata. Envelopes were opened after baseline testing by staff not involved with primary issue measure out testing. Psychometric and cardiorespiratory practise testers were blinded to the participant's intervention arm at all times. Exercise trainers and report staff asked almost adverse events at every contact. Severity and relationship of adverse events to intervention was determined by an un-blinded clinician investigator. An contained safety committee reviewed adverse events quarterly.

Consequence measures

Our primary issue measures of interest included co-primary composite scores of memory and executive office domains. These outcome measures represent our single main outcome upon which the study was powered. Our secondary aim focused on testing the consequence of exercise on function (Disability Assessment of Dementia [DAD]) and depressive symptoms (Cornell Scale for Low). Nosotros did not arrange for multiple testing equally this study was designed and funded as a pilot report to generate data for designing more definitive trial.

A comprehensive cerebral exam bombardment was given at baseline and repeated at Week thirteen and Week 26, employing validated, alternating versions of tests every other visit. Based on recent recommendations,[30] our primary outcome analyses used standardized composite scores of retention and executive function (S1 Table).[31] Planned tests for the memory composite score were Logical Memory (Immediate and Delayed), Free and Cued Selective Reminding Test (sum of free recall), and Boston Naming Test. Based upon recent work noting uncertain psychometric properties [32] and to be consistent with existing composite factors,[33] we removed Boston Naming Test from our composite memory score. The Executive Function composite score was comprised of Digit Span (Forrard and Backward), Category Fluency, D-KEFS Confirmed Right and Costless Card Sorting, Letter Number Sequencing and Stroop Colour-Discussion Interference.

We created composite cognitive scores by averaging standardized scores within each domain. Raw scores were standardized to the mean and standard deviation of good for you older adult baseline scores from a companion study (M = 0, SD = i).[34] The good for you older adult sample was recruited from the same geographic distribution during the same timeframe and using similar inclusion and exclusion criteria, making it an appropriate grouping with confirmed normal cognition on which to standardize functioning as has been done previously.[33] On rare occasions (encounter S2 Tabular array), participants were unable to complete a test due to the severity of their cognitive impairment. In these cases the score representing the everyman performance was given. When participants withdrew from the report, tests were marked every bit missing.

Our outcome measure of depression was the Cornell Scale for Low in Dementia equally rated by the caregiver.[35] Our outcome measure of functional ability was the Disability Assessment for Dementia, which asks the caregiver to assess independence in activities of daily living in the previous two weeks.[36]

We assessed cardiorespiratory fitness at baseline and Week 26 as the highest oxygen consumption attained (peak VOii) during cardiorespiratory practise testing on a treadmill to maximal chapters or volitional termination.[37] Dual x-ray absorptiometry was performed (Prodigy, GE Healthcare, Milwaukee, WI) to allow for normalization of superlative VO2 to lean mass.[eleven, 38] Nosotros normalized to lean mass because muscle accounts for the majority of oxygen uptake during do.[eleven, 39] The half-dozen-minute walk test was performed equally a secondary measure of functional fitness in a quiet, 100' hallway.[40]

MRI was performed at baseline and following the intervention in a Siemens three.0 Tesla scanner. We obtained a loftier-resolution T1 weighted image (MP-RAGE; 1x1x1mm voxels; TR = 2500ms, TE = iv.38ms, TI = 1100ms, FOV 256mmx256mm with 18% oversample, 1mm piece thickness, 8 degree flip angle) for detailed anatomical assessment. We used the Freesurfer image analysis suite (http://surfer.nmr.mgh.harvard.edu/) for volumetric segmentation optimized for longitudinal data,[41] extracting hippocampal and total gray matter volume as exploratory measures of brain health.

Intervention

Participants were asked not to alter current physical activities other than those prescribed past the report team. The AEx group began the intervention with a weekly goal of 60min in Week 1 and increased their weekly practise duration by approximately 21min per week until they achieved the current public health recommended target duration of 150min per calendar week, distributed over three–five sessions. Target middle charge per unit (HR) zones were gradually increased from twoscore–55% to 60–75% of HR reserve based on resting and height 60 minutes during cardiorespiratory fitness testing. Hour was monitored at the YMCA by conventions chest worn sensor (F4 or FT4, Polar Electro, Inc. Lake Success, NY). Total do duration and a rating of perceived exertion (Borg half dozen–xx) were gathered during each session. Exercise trainers supervised all practice sessions during Weeks ane–vi and gradually reduced supervised sessions to 1 per week based on perceived ability to be safe and independent and in consultation with the participant's written report partner and study staff.

The ST group performed a serial of non-aerobic exercises that rotated weekly (cadre strengthening, resistance bands, modified tai chi, modified yoga). As in several previous studies [42–46] we chose an active command intervention (ST) to account for potential furnishings of social engagement and concrete activity.[47] Participants in the ST grouping wore HR monitors and were asked to keep their HR beneath 100 beats per minute. Exercise trainers helped participants adjust do intensity to reduce HR every bit necessary. Like to the AEx group, trainers supervised all exercise sessions during Weeks one–6 and gradually reduced supervised sessions to 1 per week based on perceived ability to exist safe and independent and in consultation with the participant's written report partner and study staff.

To standardize implementation of the intervention protocols a training manual was developed for practise trainers. Study staff performed in-person training of the exercise trainers. This grooming was reinforced at the time of enrollment of new participants at which fourth dimension the exercise trainer, study coordinator, and participant met at the YMCA to review the intervention. Study staff also performed bi-weekly visits to YMCA facilities to monitor allegiance to the intervention protocols. This training method has been used in a previous written report and shown to rigorously control intervention.25

Assay

We performed a linear mixed-furnishings analysis of the effect of handling arm on our primary outcomes using R[48] and the lme4 packet to allow for missing information due to withdrawal.[49] Participants were included in analyses regardless of protocol adherence. We entered Treatment Arm (AEx, ST), Timepoint (Baseline, Week xiii, Week 26) and Didactics into the model as fixed furnishings and included random intercepts for participants. P-values were obtained by likelihood ratio tests of the full model including the interaction of Timepoint and Treatment Arm against the model without the interaction. We followed a similar procedure for secondary measures (east.g. peak VO2, brain volumes) with only Baseline and Calendar week 26 timepoints. Analyses were conducted with α = 0.05 to protect against Type I error. To estimate the consequence sizes of our outcomes, nosotros calculated estimated deviation between groups at Week 26, adjusted for education.

To explore the hypothesis that any benefits would exist proportional to cardiorespiratory fitness gain we too performed a multi-step, hierarchical linear regression of our primary and secondary outcomes against change in peak VOii after correcting for age, sex, education.

Results

Participants

A full of 248 individuals were assessed for study eligibility. The flow of participants through screening to enrollment is shown in Fig 1. Participants (n = 76) were randomized to either the ST (n = 37) or AEx (n = 39) intervention groups. A total of 68 participants (89%: ST due north = 34, AEx north = 34) completed the study. Demographic and baseline characteristics are given in Table 1. Participants in the two groups did non significantly differ in these measures.

thumbnail

Fig 1. Report enrollment flow.

CPX = cardiopulmonary exercise test, MRI = magnetic resonance imagery, AEx = Aerobic practise status, ST = stretching and toning control condition, AD = Alzheimer'south affliction.

https://doi.org/10.1371/periodical.pone.0170547.g001

Adherence to practise protocol

The ST grouping averaged 79.9% (SD 20%) of the prescribed practice dose as measured past total prescribed minutes of exercise and the AEx group completed 85% (SD 35%) of the prescribed exercise dose.

Outcomes of involvement

There was no apparent event of intervention on master outcome measures of Retentiveness and Executive Office or in depressive symptoms (Table 2). AEx was associated with a small gain in functional ability (Disability Assessment for Dementia) compared to individuals in the ST grouping (Ten2 = 8.2, p = 0.02). Estimated primary outcome effects of the difference betwixt groups at Week 26, adjusted for instruction tin can be found in S3 Table.

Secondary outcomes

Nosotros next assessed intervention effects on secondary consequence measures of cardiorespiratory fitness (summit VO2 and the 6-minute walk test) and brain structure (bilateral hippocampal volume and total grayness matter). AEx was associated with increased operation on the six-minute walk compared to ST (Timepoint by Treatment Arm interaction, Xii = 0.003) although AEx was not associated with benefits on other secondary measures (Table iii). Estimated secondary outcome furnishings of the difference betwixt groups at Week 26, adjusted for education, can be found in S4 Tabular array.

To explore possible fettle-specific effects, we too examined the human relationship of change in cardiorespiratory fettle (meridian VO2) with changes observed in issue measures in the overall group (as both treatment arms were active interventions) and within intervention groups (Table 4 and Fig two). For the overall group, change in acme VO2 was associated with change in the retentiveness blended score (p = 0.003) and modify in bilateral hippocampal volume (p = 0.03, Fig 2). Within group analyses demonstrated that cardiorespiratory fitness was primarily related to changes in memory performance and hippocampal volume in the AEx grouping (Table iv).

thumbnail

Fig 2.

Relationship of modify in peak VOii with change in (A) memory composite score and (B) bilateral hippocampal book. Blueish information points correspond the aerobic exercise grouping. Green data points represent the stretching and toning command group.

https://doi.org/10.1371/periodical.pone.0170547.g002

Adverse events

At that place were 25 adverse events possibly or definitely related to the intervention or cardiorespiratory practise testing: 7 mild, 2 moderate and 1 severe in the ST group and xiv mild and 1 of moderate severity in the AEx group. Common balmy adverse events possibly or probably related to the intervention included depression back, hip, articulatio genus or foot pain. Moderate severity agin events included lower extremity hurting (n = four), heart rhythm abnormalities (n = 3), and breast pain (n = 1). The astringent event was back hurting related to spinal stenosis peradventure exacerbated by exercise.

Discussion

This pilot, randomized, controlled trial provides preliminary evidence that 6-months of AEx benefits functional ability in early-phase AD compared to a ST control intervention. Furthermore, we found evidence that improvements in cardiorespiratory fitness were related to benefits in retentivity operation and brain volume change. These data fit with a growing body of evidence that enhancing cardiorespiratory fitness through exercise may exist important in attaining maximal brain benefits of do.[18, 34, 43, fifty, 51]

Our principal finding is that 26 weeks of AEx was associated with increased functional ability compared to the ST control. Our measure of functional ability was the Disability Assessment for Dementia, a caregiver-based assessment of activities of daily living, that predicts earlier fourth dimension to institutionalization.[52] Individuals with balmy to moderate Advertizing typically pass up approximately one bespeak per month on this scale (100 equates to full functional power).[36] We found that the AEx group increased 1.v points while the ST grouping decreased 4.5 points over the class of the intervention suggesting a meaningful result on sustained independence. This besides extends prior findings suggesting that exercise promotes role in Advertising.[21, 53]

We too constitute that practise-related modify in the gold standard measure of cardiorespiratory fitness (peak VO2) was related to change in both memory performance and bilateral hippocampal volume. This observation supports the concept, reported widely in creature information, that exercise may attenuate AD-related brain and cognitive decline although CR fitness gains may exist necessary to accomplish these benefits These findings thus support the cardiorespiratory fitness hypothesis,[42] which posits that improved fitness as a upshot of aerobic exercise is essential and causally related to attaining practice-related cerebral benefits. The cardiorespiratory fitness hypothesis is also supported by man studies that propose cardiorespiratory fitness gains may be important in mediating physiological benefits to brain health.[18, 34] Gains in cardiorespiratory fitness may reverberate complex systemic changes necessary to bear upon encephalon physiology or reverberate an private's power to achieve sufficient levels of do necessary to bear upon encephalon construction and role.

Surprisingly, we did not find meaning grouping differences in practise-related gains in cardiorespiratory fettle (superlative VO2) for the AEx grouping (3% gain) compared to the ST group (0.03%). The minor three% gain in cardiorespiratory fitness for the AEx group is lower than what we achieve in cognitively normal older adults following a similar protocol [34] despite good compliance with the exercise protocol and an increase in our secondary measure of functional fitness, the 6-infinitesimal walk test. This lack of a robust summit VO2 response suggests that individuals with early on Advertising may have a limited, or more variable, physiologic response to aerobic exercise than cognitively normal individuals. Nosotros have previously reported that individuals with Advertisement exhibit lower cantankerous-sectional peak VOii and significantly greater longitudinal top VO2 decline than cognitively normal older adults.[12] This suggests that there may be inherent physiological differences, beyond behavioral issues, that may limit cardiorespiratory fitness responses.

The chief limitation for this pilot study is a relatively small sample size that limits our ability to find significant group effects. The exercise interventions were delivered in the community, enhancing generalizability but peradventure introducing variability in execution, though we accept previously demonstrated that our community-based methods can evangelize a rigorously-controlled intervention of various practise doses producing linearly increasing responses to cardiorespiratory fitness.[34] Our findings of a relationship of change in cardiorespiratory fitness with memory change and hippocampal cloudburst are suggestive but practice non show cause and result. For example, it remains unclear whether improvement in cardiorespiratory fitness drives memory improvement or whether a decline in memory (or more severely progressive dementia) influences measured cardiorespiratory fitness as indexed by pinnacle VOii. Reverse causation cannot be ruled out as an explanation for these secondary findings, although these relationships remained significant fifty-fifty when controlling for baseline MMSE or baseline CDR (as an index of baseline disease severity). Finally, it is important to note that nosotros made no correction for multiple tests, raising the potential for faux positives. While multiple outcomes are non platonic for a clinical trial, we felt it important to explore in this pilot report the various aspects of function that take previously been shown to benefit from aerobic exercise.

In conclusion, findings from this airplane pilot randomized controlled trial were consistent with previous work showing aerobic do benefits functional ability in individuals with early on-phase Advertising. Farther, nosotros found indirect show that exercise-related increases in cardiorespiratory fitness may be important to improving retentiveness performance and reducing hippocampal atrophy. These furnishings should exist explored in a definitive trial of aerobic exercise for individuals with early-phase Advertising. We have provided issue size estimates and confidence intervals to inform these future studies.

Supporting information

Acknowledgments

We thank the staff of the YMCA of Greater Kansas Metropolis, the participants and their families for their commitment to the study. Colby Greer, William Hendry, Phyllis Switzer, Heather Anderson, Nicole Burns, Pat Laubinger and Rasinio Graves provided invaluable back up.

Author Contributions

  1. Conceptualization: EDV DKJ AVS JDM RAH WMB SAB RHS JMB.
  2. Data curation: JDM.
  3. Formal analysis: JKM EDV JDM JMB.
  4. Funding acquisition: JMB EDV RAH WMB SAB RHS.
  5. Investigation: JKM EDV DKJ AVS RAH HMW.
  6. Methodology: EDV DKJ AVS JDM RAH WMB SAB RHS JMB.
  7. Project administration: AVS EDV.
  8. Resource: JKM DKJ JDM.
  9. Supervision: JMB.
  10. Visualization: JKM EDV.
  11. Writing – original draft: JKM EDV DKJ AVS JDM RAH HMW WMB SAB RHS JMB.
  12. Writing – review & editing: JKM EDV DKJ AVS JDM RAH HMW WMB SAB RHS JMB.

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