RESEARCH ARTICLE
Moderate-to-high intensity aerobic exercise in patients with mild to moderate Alzheimer’s disease: a pilot study Kristian S. Frederiksen1, Nanna Sobol2,3, Nina Beyer2,3, Steen Hasselbalch1 and Gunhild Waldemar1,4 1
Memory Disorders Research Group, Danish Dementia Research Center, Department of Neurology, Rigshospitalet, Copenhagen, Denmark Musculoskeletal Rehabilitation Research Unit, Bispebjerg Hospital, Copenhagen, Denmark 3 Institute of Sports Medicine, Bispebjerg Hospital, Copenhagen, Denmark 4 Neurobiology Research Unit, Rigshospitalet, Copenhagen, Denmark Correspondence to: K. S. Frederiksen, E-mail: [email protected] 2
Objectives: Physical exercise may modulate neuropathology and symptoms of Alzheimer’s disease (AD). This pilot study assessed the feasibility of conducting a study of moderate-to-high intensity aerobic exercise in home-dwelling patients with mild AD. Methods: An uncontrolled preintervention-postintervention test design with a single group receiving the same intervention. A total of eight patients with mild to moderate AD from the Copenhagen Memory clinic were included in the study. The intervention lasted for 14 weeks and consisted of supervised, 1-h sessions of aerobic exercise three times per week (50-60% of heart rate reserve for a two-week adaptation period and 70-80 % of heart rate reserve for the remaining 12 weeks) Feasibility was assessed based on acceptability, including attendance and drop-out, safety, and patients’ and caregivers’ attitudes towards the intervention as well as other relevant parameters. Results: Attendance (mean, range: 90 %, 70-100 %) and retention (seven out of eight) rates were very high. No serious adverse events were observed. In general, patients and caregivers were positive towards the intervention. Conclusion: This study shows that it is feasible to conduct moderate-to-high intensity aerobic exercise in community-dwelling patients with mild AD. Our findings indicate that aspects such as a longer adaptation period, information about injury prevention, and need for involvement and support from caregivers should be addressed when planning an exercise intervention in an AD population. Copyright # 2014 John Wiley & Sons, Ltd. Key words: feasibility; dementia; intervention; aerobic exercise History: Received 13 July 2013; Accepted 3 February 2014; Published online in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/gps.4096
Introduction Physical exercise may modify symptoms in patients with Alzheimer’s disease (AD) (Forbes et al., 2008) as well as pathological changes (Adlard et al., 2005; Liang et al., 2010). The underlying mechanisms may include increased release of neurotrophic factors, modification of vascular pathology (van Praag, 2008) and a direct effect on AD specific pathology such as beta-amyloid (Adlard et al., 2005; Liang et al., 2010). Previous intervention studies in AD patients have primarily examined the effects of low-intensity
Copyright # 2014 John Wiley & Sons, Ltd.
exercise such as walking in nursing-home residents (Rolland et al., 2007; Santana-Sosa et al., 2008; Eggermont et al., 2009; Steinberg et al., 2009). Because physical fitness is correlated with brain volume, indicating a dose-response relationship (Burns et al., 2008; Vidoni et al., 2012), moderate-to-high intensity aerobic exercise may be more efficacious in modifying symptoms. One study evaluated the effect of a moderate-intensity exercise program in patients with mild cognitive impairment (Baker et al., 2010), but it is not known whether a similar program is feasible in patients with AD. AD is associated with challenges
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such as lack of motivation, memory and visuo-spatial impairment, frailty and co-morbidities, which could potentially jeopardize participation in trials of physical exercise. Non-pharmacological complex interventions such as exercise have received considerable attention in the management of symptoms in patients with AD (Sørensen et al., 2008; Yamaguchi et al., 2010). Frameworks for carrying out such complex interventions have been developed regarding design, evaluation, and reporting (Campbell et al., 2000; Boutron et al., 2008). The framework proposed by the Medical Research Council (Craig et al., 2008), emphasizes the importance of assessing the feasibility prior to conducting a full-scale randomized controlled trial (RCT) of a novel complex intervention. The primary aim of this exploratory uncontrolled pilot study was to assess whether it is feasible to carry out a RCT of moderate-to-high intensity aerobic exercise in community-dwelling patients with mildto-moderate AD. This included assessments of attendance, exercise-adherence, safety, and attitude towards the intervention of the patients and caregivers. Additionally, the aim was to assess whether the outcome measures were applicable and sensitive to change as a result of physical exercise. Methods Patients
Community-dwelling patients were recruited from the Memory Clinic at Copenhagen University Hospital, Rigshospitalet. All patients met the ICD-10 criteria for mild dementia and the NINCDS-ADRDA criteria for Alzheimer’s disease. Further inclusion criteria were (1) age between 65 and 80 years; (2) any pharmaceutical treatment that may affect cognitive function (cholinergic, SSRI treatment) to be stable for at least 3 months; (3) a contactable informant willing and able to assist the patient if needed (i.e. driving the patient to and from training sessions); (4) able to give informed consent; and (5) positive amyloid PET (as assessed with 11C-Pittsburg compound B (PiB)-PET) indicative of AD. Exclusion criteria were (1) severe physical or psychiatric illness that would prevent participation in the intervention program (i.e. heart disease, severe joint and muscle pain, psychotic, and severe depressive symptoms); (2) change in medication, which may negatively affect cognitive function (e.g. anti-cholinergic medication) within the previous three months. Copyright # 2014 John Wiley & Sons, Ltd.
The study was approved by The Capital Region Ethics Committee (H-4-2010-047) according to the Declaration of Helsinki II and all subjects gave written informed consent for participation. Study design
An uncontrolled preintervention-postintervention test design with a single group receiving the same intervention was used. Following an initial screening session, informed consent was obtained. Baseline assessments were carried out prior to the intervention and included an extensive history taking, a physical examination (including electrocardiogram and blood-pressure measurements), and administration of clinical scales. Physical assessments (including assessment of maximal oxygen uptake, maximal isometric knee extension strength, leg extension power, and functional performance, see succeeding text) were performed on a separate day. After the intervention all assessments were repeated. Intervention
The patients exercised in groups of four persons 1 h three times weekly for 14 weeks supervised by the same experienced physiotherapist. To encourage attendance, patients received information regarding the background and aim of the study and the contents of the training program in the first session. This was followed by a two-week adaptation period where the patients were introduced to the training program. The training program consisted of a 10-min warm-up including balance training followed by three 8-min bouts of aerobic exercise interspersed by two-min breaks, during which the patients were encouraged to remain warmed up. The intensity was 50% to 60% of heart rate reserve corresponding to 12 to 14 on the Borg scale (rate of perceived exertion, ) during the two-week adaptation period and 70% to 80% of heart rate reserve corresponding to 15 to 17 on the Borg scale during the remaining 12 weeks. The aerobic exercise was carried out on bicycle ergometer, cross-trainer and treadmill. The patients were encouraged to use all machines, but if one or two machines were preferred, this was accepted. Perceived exertion (Borg scale) and data on maximal HR during the baseline test of maximal oxygen uptake was used to ensure that the patients exercised with the intended training intensity. Perceived exertion to help monitoring training intensity was used because a number of patients with AD are medicated with Beta–blockers, which reduces the heart Int J Geriatr Psychiatry 2014
Feasibility study of exercise in AD
rate. Each training session ended with low load exercises for quadriceps, hamstrings, and calf muscles and stretching as part of the 10-min cool-down. Assessment of feasibility
Feasibility was assessed based on the overall ability of conducting the study including safety, acceptability, improvements in physical capacity, and the participants’ ability to complete the physical tests. Safety was assessed based on the occurrence of adverse events (AE) and serious adverse events (SAE, i.e., AEs leading to e.g., hospitalization and death). Acceptability was assessed on the basis of attendance rate, level of training intensity achieved (% of heart rate reserve and perceived exertion), number of drop-outs, and self-report. Furthermore, the ability of the clinical outcome measures to assess change over time (i.e., absence of floor or ceiling effects) was evaluated. Focus group interview and questionnaire
Following the intervention focus-group interviews were conducted with patients and their caregivers, respectively, as a part of the process evaluation (Oakley et al., 2006; Craig et al., 2008). Interview-themes included potential barriers to participation, how the intervention was perceived, and potential additional needs of the patients. The interviewer who had extensive experience with interviewing people with dementia was not otherwise involved in the study. Finally, information regarding the experience of intensity and duration of the training program was obtained through questionnaires filled out by patients and caregivers, respectively. Clinical outcome measures
The mini mental state examination (MMSE) (M. F. Folstein et al., 1975), which measures global cognitive function, and the Symbol Digit Modalities Test (SDMT) (Smith, 1973), which measures processing speed and executive function, were administered. The SDMT scores were obtained after 90 and 120 s. The Geriatric Depression Scale-15 items (Sheikh, 1986) was used to assess the presence of depressive symptoms. The caregiver completed the Alzheimer’s Disease Cooperative Study Activities of Daily Living scale to assess ADL function (Galasko et al., 1997). Both the patient and proxy version of The quality of life in AD (Logsdon et al., 2002) was used to assess quality of life. Copyright # 2014 John Wiley & Sons, Ltd.
Measurement of maximal oxygen uptake was performed on a bicycle ergometer (Monark Ergomedic 839E, Monark Exercise AB, Sweden). Before the graded exercise test, the participants bicycled for 6 min at 25 W (females) and 50 W (males) and the average heart rate during the last minute was recorded. This was followed by a graded bicycle ergometer exercise test to determine maximal oxygen uptake (VO2max) using a pedaling frequency of 60 RPM and an increase in power by 25 W every minute. Expired gases were collected on-line and analyzed. Maximal isometric knee extension strength was measured at an angle of 60° of knee flexion (0° = full extension) in a dynamometer (Good Strength GS-100, MetiturOy, Finland). Maximal single leg extensor power was measured using a Nottingham leg extensor powerrig® (Bassey and Short, 1990). Handgrip strength of each hand was measured using a Jamar® dynamometer (Roberts et al., 2011). Functional performance was assessed by the Short Physical Performance Battery (SPPB)(J M Guralnik et al., 1994), which has been used in studies on older people with cognitive dysfunction (Carmelli et al., 2000). SPPB assesses balance, gait speed, and lower extremity strength (score from 0 to 12). In addition, the 30-s chair stand test (number of chair stands in 30 seconds) was performed (Rikli and Jones, 1999). Statistical analysis
Data are presented as mean (standard deviation (SD)). Effects of the intervention were tested using paired samples t-test or the Wilcoxon signed-rank test as appropriate. Statistical analyses were carried out using Intercooled Stata 9.2 for Macintosh (Stata corporation, USA). Level of significance was set at p = 0.05 (two-tailed). Results Ten patients were eligible for inclusion and gave informed consent. Prior to initiation of the intervention, one patient had to be excluded because of very low 11C-PiB retention and one because of an unrecognized atrial fibrillation. See Table 1 for Baseline characteristics. Moreover, one subject dropped out of the intervention after approximately 10 weeks. This patient underwent all the postintervention assessments except the physical tests. A second patient did not complete the follow-up. The median time from baseline assessment to intervention was 4 days (range 0-5 days). Int J Geriatr Psychiatry 2014
K. S. Frederiksen et al. Table 1 Baseline demographics and change scores for clinical characteristics Mean difference (SD) Age, years Gender, f/m MMSEa SDMT 90 s a SDMT 120 s a QoL-AD patient a QoL-AD proxy a ADCS-ADL a GDS-15 b
71.9 (5.4) 6/2 24.3 (4.4) 17.4 (4.0) 22.9 (5.3) 37.4 (5.7) 39.3 (5.7) 69.6 (5.5) 3.1 (2.2)
N/A N/A 1.4 (3.3) 3.1 (3.5) 4.4 (4.1) 0.4 (2.9) 3.4 (1.7) 3.1 (5.7) 1 (1)
p-value N/A N/A 0.3 0.06 0.03 0.7 0.002 0.19 0.04
AD, Alzheimer’s disease; MMSE, mini mental state examination; SDMT, symbol digit modalities test; QoL-AD patient, quality of life in AD patient-rated; QoL-AD proxy, quality of life in AD proxyrated; ADCS-ADL, Alzheimer’s disease cooperative study-activities of daily living scale; GDS-15, Geriatric Depression Scale 15 items. The table shows baseline demographics and clinical characteristics for all patients( n = 8). Change scores for all patients followed up (n = 7). P-values are for Student’s t-test for paired samples. a Higher score = better function, b Lower score = fewer symptoms
Feasibility
Mean session–attendance rate was 90 % (Range 75-100%). The physiotherapist had to phone one participant prior to each session to ensure that the participant remembered to attend. Moreover, most patients needed support from caregivers to attend (e.g. helping them with transport and with remembering to attend the training). All patients were able to achieve the intended training intensity (70-80% of heart rate reserve or Borg 15-17) on all three exercise machines. Two patients with the lowest MMSE at baseline (18 and 19, respectively) needed extra instructions and supervision in using the machines. Four patients found the training acceptable, two thought it was too strenuous and one patient felt that the training frequency was too high. All patients liked training on the cross-trainer, whereas only four preferred training on the treadmill and three on the bicycle ergometer. No adverse events (such as fainting, falls, or muscle fiber rupture) were observed during training sessions. However, two patients reported knee pain, which they attributed to the training. These joint problems were most likely because of overuse because the patients took up additional training activities between training sessions. One of the patients who reported knee pain had a 10-year-old knee replacement and dropped out of the intervention after 10 weeks, resulting in a retention rate of 7 out of 8. On the day of post-test, a patient had experienced a fall unrelated to the training prior to assessment. No AEs could be classified as SAEs. Copyright # 2014 John Wiley & Sons, Ltd.
In the focus-group interviews, both patients and caregivers reported a positive experience with the intervention. However, the patients would have preferred more information about the exercise program and information about prevention of overuse injury prior to the training period. In addition, both patients and caregivers expressed the need for a longer adaptation period. The intervention was perceived as very time consuming, which resulted in decreased participation in other activities. Moreover, increased tiredness of the participants was reported by both caregivers and participants, and this may also have contributed to the decreased participation in other activities. Surprisingly, transportation to the training facility was not a barrier for participation. Motivational factors for participation and adherence included a hope that the exercise would slow down the disease progression, benefit for future patients, and the social aspect of training. In general, patients and caregivers reported that physical fitness but not memory had improved. Clinical outcomes
All participants were able to understand the instructions given in relation to the clinical outcome measures and complete the scales and tests for cognitive and physical function in a manner which did not compromise their validity. We observed a potential ceiling effect regarding SPPB with all participants scoring either 11 or 12 (max. score = 12). No other potential flooring or ceiling effects were observed. For further results, see Tables 1 and 2. Discussion This pilot study showed that a 14-week program of supervised moderate-to-high intensity aerobic exercise in community-dwelling patients with mild to moderate AD is feasible and safe. We found a high rate of adherence, a low drop-up rate, and observed no serious adverse events. The high attendance rate indicated that the number of sessions per week, the duration of the training sessions, and the length of the training period were acceptable, and are comparable with previous rates reported in a similar population, which investigated a less intensive but longer intervention (Fang et al., 2011). It is likely that the high attendance rate was partly because of the caregivers who facilitated participation (transport, reminding patients to attend). This emphasizes the importance of support from caregivers or other measures that can support the participation Int J Geriatr Psychiatry 2014
Feasibility study of exercise in AD Table 2 Aerobic fitness and muscle strength (n = 6)
VO2peak (ml/kg/min) Respiratory exchange rate Heart rate response Isometric quad strength (N) Right leg Left leg Leg extension power (W/kg) Right leg Left leg Handgrip (Kg) Right hand Left hand Short physical performance battery 30 s chair stand
Pre-test
Post-test
p-value
25.2 (5.7) 1.14 (0.05)
25.9 (5.3) 1.21 (0.10)
0.07 0.12
95.4 (9.0)
91.1 (8.9)
0.03
303.4 (72.1) 315.8 (80.8)
351.6 (44.6) 333.0 (30.8)
0.08 0.50
2.18 (0.4) 2.10 (0.5)
2.30 (0.5) 2.12 (0.5)
0.03 0.86
29.5 (7.3) 27.2 (9.8) 11.5 (0.7)
29.0 (6.8) 28.0 (6.6) 11.2 (1.2)
0.61 0.68 0.36
14.7 (1.7)
14.0 (2.8)
0.56
The table shows mean (±SD) for preintervention and postintervention results of measures of aerobic fitness and muscle strength. p-values are for Wilcoxon signed-rank test.
of the patient. Consequently, future studies should assess the burden for caregivers of patients participating in such interventions, because it is unavoidable that participation requires additional support from caregivers. The focus group interview revealed that the most important barrier for participation was that the intervention was time consuming. Other studies, which have applied training programs consisting of 3-5 sessions per week, have not reported similar concerns from participants (Santana-Sosa et al., 2008; Eggermont et al., 2009). This may be because the participants in the present study were communitydwelling, and therefore spent time getting to and from the training facility, as opposed to nursing home residents, who trained within the place of residence (Eggermont et al., 2009). We also found that participants reported that activities outside the study decreased because of time spent on the intervention, possibly compounded by increased tiredness. It is concerning that the intervention possibly led to a decrease in participation in other activities. To our knowledge, no other study has reported this unwanted effect of exercise intervention. It may be speculated that community-dwelling patients as opposed to nursing home residents may be involved in more activities, which possibly would account for our findings, but also that other studies have not assessed whether such effects may be present. However, one other study in community-dwelling AD patients did not report increased tiredness (Fang et al., 2011), although no interview results examining this was reported. Another Copyright # 2014 John Wiley & Sons, Ltd.
aspect that may have impacted our findings is that the intensity of the training in this study was higher than in previously reported studies (Teri et al., 2003; Rolland et al., 2007; Santana-Sosa et al., 2008; Eggermont et al., 2009; Steinberg et al., 2009) and consequently may have unintended effects, which are not encountered at lower exercise intensities. It highlights a possible trade-off between a biological effect of exercise on brain structures (Vidoni et al., 2012), which may be governed by a dose-response relationship where higher intensity is more beneficial, and a similar but reverse relationship between intensity and factors such as finding the intervention enriching and fun. Two patients reported knee pain and one dropped out. This may indicate that more information regarding prevention of injuries is needed as also indicated by the interviews because patients in general had little knowledge of this. Moreover, a longer adaptation period may be needed to reduce the risk of over use injuries. We did not observe any serious adverse events, which is in-line with previous studies (Rolland et al., 2007; Santana-Sosa et al., 2008; Steinberg et al., 2009). However, these studies used lower-intensity exercise, which may have a different safety profile compared with the higher intensity exercise in the present study, and in addition, they were conducted in a different patient population, that is, nursing home residents. Training on the exercise machines was well tolerated, and all patients reached their aerobic target zone. In general, the patients were able to understand and follow the instructions given by the physiotherapist during training sessions, but the participants with a lower MMSE score needed additional supervision. Consequently, including patients with more advanced disease may require other types of exercises or exercise machines. Other intervention studies have primarily relied on walking as an exercise intervention. Therefore, the novel finding in our study is that exercise in standard equipped gyms at a relatively high intensity is feasibile for patients with AD as long as appropriate instruction and supervision is available. When considering the generalizability of our findings with regards to acceptability and safety of the intervention, it is important to be aware that the patients were highly selected, because patients with serious medical conditions and patients who were not motivated to exercise were not included. This was carried out to increase the likelihood of participants completing the intervention and to minimize safety issues for participants. All patients were able to follow instructions regarding the completion of the scales and tests, including Int J Geriatr Psychiatry 2014
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those who tested physical function. We observed neither ceiling nor floor effects in any of the tests applied in this study, except the SPPB. To avoid similar ceiling effects, more challenging functional performance tests should be implemented in future RCTs. The study was not designed to evaluate the effect of the exercise intervention. However, the postintervention decrease in heart rate at the same submaximal intensity during the 6-min bicycling prior to the graded exercise test indicate that endurance may have improved as a result of the intervention. The improvement may have been underestimated because of a too low intensity as indicated by the low HR level in three of the subjects (left panel, Figure 1). To avoid this, the initial intensity level needs to be increased. On the other hand, the borderline significant change in VO2peak may be because the increments in the graded test were too high (25 W every minute), resulting in inability to keep the cadence because of thigh muscle fatigue. Increments of 20 W every minute may be more appropriate in this patient group. The intervention was not expected to have any effect on hand grip strength in contrast to quadriceps strength and muscle power. The results regarding quadriceps strength and muscle power in the right leg may indicate a potential effect of the intervention. The lack of change in the left leg may be because two out of six participants reported knee pain in their left leg on the day of post-test (because of a fall and an overuse injury) In general, the intervention appeared to have a positive effect on the participants’ physical function, indicating that the training intensity, frequency, and duration were adequate.
The strengths of this study are that the experience of the participants and caregivers and their perception of the intervention were obtained through a focusgroup interview and a questionnaire. This enabled a qualitative study of patient and caregiver attitude towards the intervention. In our case, this methodology revealed important aspects relevant to all researchers planning a similar complex intervention in patients with dementia. This study has some limitations. The study was per design not powered to test effectiveness of the intervention. Our design did not enable assessments of certain important aspects of an RCT such as the randomization process because a control group was not included. In addition, the single-center design did not allow us to test how a multicenter setting will function. In conclusion, our findings support that it is feasible and safe to carry out a study of moderate-to-high intensity aerobic exercise in community-dwelling patients with mild to moderate AD. To reduce the risk of over use injury, extensive information about prevention of such injuries should be provided. Moreover, an adaptation period of more than 2 weeks with added emphasis on strength training appears advisable. Caregiver involvement, which is crucial for high attendance rates, should be supported, and structures to support caregivers in this role should be considered. Although patients in our study were able to use standard exercise equipment those with more advanced disease (e.g. as indicated by MMSE < 20) may need more supervision, and this should be considered in future studies. The use of a focus-group interview coupled with a questionnaire is useful for exploring
Figure 1 Heart during 6 min of bicycling and peak oxygen uptake.
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Feasibility study of exercise in AD
important issues related to feasibility. Finally, with regards to assessment of physical function, evidence of ceiling effects indicates that more challenging physical performance tests need to be implemented in this patient group. Conflict of interest None declared.
Key points Assessing the efficacy of non-pharmacological complex interventions such as aerobic exercise presents unique challenges, which requires careful assessment of feasibility. Moderate-to-high intensity aerobic exercise seems safe and feasible to apply in an interventional study in mild AD. To ensure a high rate of retention and participation, caregiver involvement is important. Studies testing other non-pharmacological complex interventions should consider including piloting with semi-quantitative interviews in the assessment of feasibility, because this may help uncover important aspects of a planned intervention.
• • • •
Acknowledgements This study was financially supported via a grant from the Danish Strategic Research Council as a part of the Preserving quality of life, physical health and functional ability in Alzheimer’s disease: the effect of physical exercise (ADEX) initiative. The project was partly supported with funds from the Association of Danish Physiotherapists, and the Faculty of Health Sciences, Copenhagen University. We would also like to cordially thank nurse Lis Christoffersen for conducting the focus-group interview with patients and caregivers. References Adlard P, Perreau VM, Pop V, Cotman CW. 2005. Voluntary exercise decreases amyloid load in a transgenic model of Alzheimer’s disease. J neurosci 25(17): 4217–4221.
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Moderate-to-high intensity aerobic exercise in patients with mild to moderate Alzheimer’s disease: a pilot study Kristian S. Frederiksen1, Nanna Sobol2,3, Nina Beyer2,3, Steen Hasselbalch1 and Gunhild Waldemar1,4 1
Memory Disorders Research Group, Danish Dementia Research Center, Department of Neurology, Rigshospitalet, Copenhagen, Denmark Musculoskeletal Rehabilitation Research Unit, Bispebjerg Hospital, Copenhagen, Denmark 3 Institute of Sports Medicine, Bispebjerg Hospital, Copenhagen, Denmark 4 Neurobiology Research Unit, Rigshospitalet, Copenhagen, Denmark Correspondence to: K. S. Frederiksen, E-mail: [email protected] 2
Objectives: Physical exercise may modulate neuropathology and symptoms of Alzheimer’s disease (AD). This pilot study assessed the feasibility of conducting a study of moderate-to-high intensity aerobic exercise in home-dwelling patients with mild AD. Methods: An uncontrolled preintervention-postintervention test design with a single group receiving the same intervention. A total of eight patients with mild to moderate AD from the Copenhagen Memory clinic were included in the study. The intervention lasted for 14 weeks and consisted of supervised, 1-h sessions of aerobic exercise three times per week (50-60% of heart rate reserve for a two-week adaptation period and 70-80 % of heart rate reserve for the remaining 12 weeks) Feasibility was assessed based on acceptability, including attendance and drop-out, safety, and patients’ and caregivers’ attitudes towards the intervention as well as other relevant parameters. Results: Attendance (mean, range: 90 %, 70-100 %) and retention (seven out of eight) rates were very high. No serious adverse events were observed. In general, patients and caregivers were positive towards the intervention. Conclusion: This study shows that it is feasible to conduct moderate-to-high intensity aerobic exercise in community-dwelling patients with mild AD. Our findings indicate that aspects such as a longer adaptation period, information about injury prevention, and need for involvement and support from caregivers should be addressed when planning an exercise intervention in an AD population. Copyright # 2014 John Wiley & Sons, Ltd. Key words: feasibility; dementia; intervention; aerobic exercise History: Received 13 July 2013; Accepted 3 February 2014; Published online in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/gps.4096
Introduction Physical exercise may modify symptoms in patients with Alzheimer’s disease (AD) (Forbes et al., 2008) as well as pathological changes (Adlard et al., 2005; Liang et al., 2010). The underlying mechanisms may include increased release of neurotrophic factors, modification of vascular pathology (van Praag, 2008) and a direct effect on AD specific pathology such as beta-amyloid (Adlard et al., 2005; Liang et al., 2010). Previous intervention studies in AD patients have primarily examined the effects of low-intensity
Copyright # 2014 John Wiley & Sons, Ltd.
exercise such as walking in nursing-home residents (Rolland et al., 2007; Santana-Sosa et al., 2008; Eggermont et al., 2009; Steinberg et al., 2009). Because physical fitness is correlated with brain volume, indicating a dose-response relationship (Burns et al., 2008; Vidoni et al., 2012), moderate-to-high intensity aerobic exercise may be more efficacious in modifying symptoms. One study evaluated the effect of a moderate-intensity exercise program in patients with mild cognitive impairment (Baker et al., 2010), but it is not known whether a similar program is feasible in patients with AD. AD is associated with challenges
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such as lack of motivation, memory and visuo-spatial impairment, frailty and co-morbidities, which could potentially jeopardize participation in trials of physical exercise. Non-pharmacological complex interventions such as exercise have received considerable attention in the management of symptoms in patients with AD (Sørensen et al., 2008; Yamaguchi et al., 2010). Frameworks for carrying out such complex interventions have been developed regarding design, evaluation, and reporting (Campbell et al., 2000; Boutron et al., 2008). The framework proposed by the Medical Research Council (Craig et al., 2008), emphasizes the importance of assessing the feasibility prior to conducting a full-scale randomized controlled trial (RCT) of a novel complex intervention. The primary aim of this exploratory uncontrolled pilot study was to assess whether it is feasible to carry out a RCT of moderate-to-high intensity aerobic exercise in community-dwelling patients with mildto-moderate AD. This included assessments of attendance, exercise-adherence, safety, and attitude towards the intervention of the patients and caregivers. Additionally, the aim was to assess whether the outcome measures were applicable and sensitive to change as a result of physical exercise. Methods Patients
Community-dwelling patients were recruited from the Memory Clinic at Copenhagen University Hospital, Rigshospitalet. All patients met the ICD-10 criteria for mild dementia and the NINCDS-ADRDA criteria for Alzheimer’s disease. Further inclusion criteria were (1) age between 65 and 80 years; (2) any pharmaceutical treatment that may affect cognitive function (cholinergic, SSRI treatment) to be stable for at least 3 months; (3) a contactable informant willing and able to assist the patient if needed (i.e. driving the patient to and from training sessions); (4) able to give informed consent; and (5) positive amyloid PET (as assessed with 11C-Pittsburg compound B (PiB)-PET) indicative of AD. Exclusion criteria were (1) severe physical or psychiatric illness that would prevent participation in the intervention program (i.e. heart disease, severe joint and muscle pain, psychotic, and severe depressive symptoms); (2) change in medication, which may negatively affect cognitive function (e.g. anti-cholinergic medication) within the previous three months. Copyright # 2014 John Wiley & Sons, Ltd.
The study was approved by The Capital Region Ethics Committee (H-4-2010-047) according to the Declaration of Helsinki II and all subjects gave written informed consent for participation. Study design
An uncontrolled preintervention-postintervention test design with a single group receiving the same intervention was used. Following an initial screening session, informed consent was obtained. Baseline assessments were carried out prior to the intervention and included an extensive history taking, a physical examination (including electrocardiogram and blood-pressure measurements), and administration of clinical scales. Physical assessments (including assessment of maximal oxygen uptake, maximal isometric knee extension strength, leg extension power, and functional performance, see succeeding text) were performed on a separate day. After the intervention all assessments were repeated. Intervention
The patients exercised in groups of four persons 1 h three times weekly for 14 weeks supervised by the same experienced physiotherapist. To encourage attendance, patients received information regarding the background and aim of the study and the contents of the training program in the first session. This was followed by a two-week adaptation period where the patients were introduced to the training program. The training program consisted of a 10-min warm-up including balance training followed by three 8-min bouts of aerobic exercise interspersed by two-min breaks, during which the patients were encouraged to remain warmed up. The intensity was 50% to 60% of heart rate reserve corresponding to 12 to 14 on the Borg scale (rate of perceived exertion, ) during the two-week adaptation period and 70% to 80% of heart rate reserve corresponding to 15 to 17 on the Borg scale during the remaining 12 weeks. The aerobic exercise was carried out on bicycle ergometer, cross-trainer and treadmill. The patients were encouraged to use all machines, but if one or two machines were preferred, this was accepted. Perceived exertion (Borg scale) and data on maximal HR during the baseline test of maximal oxygen uptake was used to ensure that the patients exercised with the intended training intensity. Perceived exertion to help monitoring training intensity was used because a number of patients with AD are medicated with Beta–blockers, which reduces the heart Int J Geriatr Psychiatry 2014
Feasibility study of exercise in AD
rate. Each training session ended with low load exercises for quadriceps, hamstrings, and calf muscles and stretching as part of the 10-min cool-down. Assessment of feasibility
Feasibility was assessed based on the overall ability of conducting the study including safety, acceptability, improvements in physical capacity, and the participants’ ability to complete the physical tests. Safety was assessed based on the occurrence of adverse events (AE) and serious adverse events (SAE, i.e., AEs leading to e.g., hospitalization and death). Acceptability was assessed on the basis of attendance rate, level of training intensity achieved (% of heart rate reserve and perceived exertion), number of drop-outs, and self-report. Furthermore, the ability of the clinical outcome measures to assess change over time (i.e., absence of floor or ceiling effects) was evaluated. Focus group interview and questionnaire
Following the intervention focus-group interviews were conducted with patients and their caregivers, respectively, as a part of the process evaluation (Oakley et al., 2006; Craig et al., 2008). Interview-themes included potential barriers to participation, how the intervention was perceived, and potential additional needs of the patients. The interviewer who had extensive experience with interviewing people with dementia was not otherwise involved in the study. Finally, information regarding the experience of intensity and duration of the training program was obtained through questionnaires filled out by patients and caregivers, respectively. Clinical outcome measures
The mini mental state examination (MMSE) (M. F. Folstein et al., 1975), which measures global cognitive function, and the Symbol Digit Modalities Test (SDMT) (Smith, 1973), which measures processing speed and executive function, were administered. The SDMT scores were obtained after 90 and 120 s. The Geriatric Depression Scale-15 items (Sheikh, 1986) was used to assess the presence of depressive symptoms. The caregiver completed the Alzheimer’s Disease Cooperative Study Activities of Daily Living scale to assess ADL function (Galasko et al., 1997). Both the patient and proxy version of The quality of life in AD (Logsdon et al., 2002) was used to assess quality of life. Copyright # 2014 John Wiley & Sons, Ltd.
Measurement of maximal oxygen uptake was performed on a bicycle ergometer (Monark Ergomedic 839E, Monark Exercise AB, Sweden). Before the graded exercise test, the participants bicycled for 6 min at 25 W (females) and 50 W (males) and the average heart rate during the last minute was recorded. This was followed by a graded bicycle ergometer exercise test to determine maximal oxygen uptake (VO2max) using a pedaling frequency of 60 RPM and an increase in power by 25 W every minute. Expired gases were collected on-line and analyzed. Maximal isometric knee extension strength was measured at an angle of 60° of knee flexion (0° = full extension) in a dynamometer (Good Strength GS-100, MetiturOy, Finland). Maximal single leg extensor power was measured using a Nottingham leg extensor powerrig® (Bassey and Short, 1990). Handgrip strength of each hand was measured using a Jamar® dynamometer (Roberts et al., 2011). Functional performance was assessed by the Short Physical Performance Battery (SPPB)(J M Guralnik et al., 1994), which has been used in studies on older people with cognitive dysfunction (Carmelli et al., 2000). SPPB assesses balance, gait speed, and lower extremity strength (score from 0 to 12). In addition, the 30-s chair stand test (number of chair stands in 30 seconds) was performed (Rikli and Jones, 1999). Statistical analysis
Data are presented as mean (standard deviation (SD)). Effects of the intervention were tested using paired samples t-test or the Wilcoxon signed-rank test as appropriate. Statistical analyses were carried out using Intercooled Stata 9.2 for Macintosh (Stata corporation, USA). Level of significance was set at p = 0.05 (two-tailed). Results Ten patients were eligible for inclusion and gave informed consent. Prior to initiation of the intervention, one patient had to be excluded because of very low 11C-PiB retention and one because of an unrecognized atrial fibrillation. See Table 1 for Baseline characteristics. Moreover, one subject dropped out of the intervention after approximately 10 weeks. This patient underwent all the postintervention assessments except the physical tests. A second patient did not complete the follow-up. The median time from baseline assessment to intervention was 4 days (range 0-5 days). Int J Geriatr Psychiatry 2014
K. S. Frederiksen et al. Table 1 Baseline demographics and change scores for clinical characteristics Mean difference (SD) Age, years Gender, f/m MMSEa SDMT 90 s a SDMT 120 s a QoL-AD patient a QoL-AD proxy a ADCS-ADL a GDS-15 b
71.9 (5.4) 6/2 24.3 (4.4) 17.4 (4.0) 22.9 (5.3) 37.4 (5.7) 39.3 (5.7) 69.6 (5.5) 3.1 (2.2)
N/A N/A 1.4 (3.3) 3.1 (3.5) 4.4 (4.1) 0.4 (2.9) 3.4 (1.7) 3.1 (5.7) 1 (1)
p-value N/A N/A 0.3 0.06 0.03 0.7 0.002 0.19 0.04
AD, Alzheimer’s disease; MMSE, mini mental state examination; SDMT, symbol digit modalities test; QoL-AD patient, quality of life in AD patient-rated; QoL-AD proxy, quality of life in AD proxyrated; ADCS-ADL, Alzheimer’s disease cooperative study-activities of daily living scale; GDS-15, Geriatric Depression Scale 15 items. The table shows baseline demographics and clinical characteristics for all patients( n = 8). Change scores for all patients followed up (n = 7). P-values are for Student’s t-test for paired samples. a Higher score = better function, b Lower score = fewer symptoms
Feasibility
Mean session–attendance rate was 90 % (Range 75-100%). The physiotherapist had to phone one participant prior to each session to ensure that the participant remembered to attend. Moreover, most patients needed support from caregivers to attend (e.g. helping them with transport and with remembering to attend the training). All patients were able to achieve the intended training intensity (70-80% of heart rate reserve or Borg 15-17) on all three exercise machines. Two patients with the lowest MMSE at baseline (18 and 19, respectively) needed extra instructions and supervision in using the machines. Four patients found the training acceptable, two thought it was too strenuous and one patient felt that the training frequency was too high. All patients liked training on the cross-trainer, whereas only four preferred training on the treadmill and three on the bicycle ergometer. No adverse events (such as fainting, falls, or muscle fiber rupture) were observed during training sessions. However, two patients reported knee pain, which they attributed to the training. These joint problems were most likely because of overuse because the patients took up additional training activities between training sessions. One of the patients who reported knee pain had a 10-year-old knee replacement and dropped out of the intervention after 10 weeks, resulting in a retention rate of 7 out of 8. On the day of post-test, a patient had experienced a fall unrelated to the training prior to assessment. No AEs could be classified as SAEs. Copyright # 2014 John Wiley & Sons, Ltd.
In the focus-group interviews, both patients and caregivers reported a positive experience with the intervention. However, the patients would have preferred more information about the exercise program and information about prevention of overuse injury prior to the training period. In addition, both patients and caregivers expressed the need for a longer adaptation period. The intervention was perceived as very time consuming, which resulted in decreased participation in other activities. Moreover, increased tiredness of the participants was reported by both caregivers and participants, and this may also have contributed to the decreased participation in other activities. Surprisingly, transportation to the training facility was not a barrier for participation. Motivational factors for participation and adherence included a hope that the exercise would slow down the disease progression, benefit for future patients, and the social aspect of training. In general, patients and caregivers reported that physical fitness but not memory had improved. Clinical outcomes
All participants were able to understand the instructions given in relation to the clinical outcome measures and complete the scales and tests for cognitive and physical function in a manner which did not compromise their validity. We observed a potential ceiling effect regarding SPPB with all participants scoring either 11 or 12 (max. score = 12). No other potential flooring or ceiling effects were observed. For further results, see Tables 1 and 2. Discussion This pilot study showed that a 14-week program of supervised moderate-to-high intensity aerobic exercise in community-dwelling patients with mild to moderate AD is feasible and safe. We found a high rate of adherence, a low drop-up rate, and observed no serious adverse events. The high attendance rate indicated that the number of sessions per week, the duration of the training sessions, and the length of the training period were acceptable, and are comparable with previous rates reported in a similar population, which investigated a less intensive but longer intervention (Fang et al., 2011). It is likely that the high attendance rate was partly because of the caregivers who facilitated participation (transport, reminding patients to attend). This emphasizes the importance of support from caregivers or other measures that can support the participation Int J Geriatr Psychiatry 2014
Feasibility study of exercise in AD Table 2 Aerobic fitness and muscle strength (n = 6)
VO2peak (ml/kg/min) Respiratory exchange rate Heart rate response Isometric quad strength (N) Right leg Left leg Leg extension power (W/kg) Right leg Left leg Handgrip (Kg) Right hand Left hand Short physical performance battery 30 s chair stand
Pre-test
Post-test
p-value
25.2 (5.7) 1.14 (0.05)
25.9 (5.3) 1.21 (0.10)
0.07 0.12
95.4 (9.0)
91.1 (8.9)
0.03
303.4 (72.1) 315.8 (80.8)
351.6 (44.6) 333.0 (30.8)
0.08 0.50
2.18 (0.4) 2.10 (0.5)
2.30 (0.5) 2.12 (0.5)
0.03 0.86
29.5 (7.3) 27.2 (9.8) 11.5 (0.7)
29.0 (6.8) 28.0 (6.6) 11.2 (1.2)
0.61 0.68 0.36
14.7 (1.7)
14.0 (2.8)
0.56
The table shows mean (±SD) for preintervention and postintervention results of measures of aerobic fitness and muscle strength. p-values are for Wilcoxon signed-rank test.
of the patient. Consequently, future studies should assess the burden for caregivers of patients participating in such interventions, because it is unavoidable that participation requires additional support from caregivers. The focus group interview revealed that the most important barrier for participation was that the intervention was time consuming. Other studies, which have applied training programs consisting of 3-5 sessions per week, have not reported similar concerns from participants (Santana-Sosa et al., 2008; Eggermont et al., 2009). This may be because the participants in the present study were communitydwelling, and therefore spent time getting to and from the training facility, as opposed to nursing home residents, who trained within the place of residence (Eggermont et al., 2009). We also found that participants reported that activities outside the study decreased because of time spent on the intervention, possibly compounded by increased tiredness. It is concerning that the intervention possibly led to a decrease in participation in other activities. To our knowledge, no other study has reported this unwanted effect of exercise intervention. It may be speculated that community-dwelling patients as opposed to nursing home residents may be involved in more activities, which possibly would account for our findings, but also that other studies have not assessed whether such effects may be present. However, one other study in community-dwelling AD patients did not report increased tiredness (Fang et al., 2011), although no interview results examining this was reported. Another Copyright # 2014 John Wiley & Sons, Ltd.
aspect that may have impacted our findings is that the intensity of the training in this study was higher than in previously reported studies (Teri et al., 2003; Rolland et al., 2007; Santana-Sosa et al., 2008; Eggermont et al., 2009; Steinberg et al., 2009) and consequently may have unintended effects, which are not encountered at lower exercise intensities. It highlights a possible trade-off between a biological effect of exercise on brain structures (Vidoni et al., 2012), which may be governed by a dose-response relationship where higher intensity is more beneficial, and a similar but reverse relationship between intensity and factors such as finding the intervention enriching and fun. Two patients reported knee pain and one dropped out. This may indicate that more information regarding prevention of injuries is needed as also indicated by the interviews because patients in general had little knowledge of this. Moreover, a longer adaptation period may be needed to reduce the risk of over use injuries. We did not observe any serious adverse events, which is in-line with previous studies (Rolland et al., 2007; Santana-Sosa et al., 2008; Steinberg et al., 2009). However, these studies used lower-intensity exercise, which may have a different safety profile compared with the higher intensity exercise in the present study, and in addition, they were conducted in a different patient population, that is, nursing home residents. Training on the exercise machines was well tolerated, and all patients reached their aerobic target zone. In general, the patients were able to understand and follow the instructions given by the physiotherapist during training sessions, but the participants with a lower MMSE score needed additional supervision. Consequently, including patients with more advanced disease may require other types of exercises or exercise machines. Other intervention studies have primarily relied on walking as an exercise intervention. Therefore, the novel finding in our study is that exercise in standard equipped gyms at a relatively high intensity is feasibile for patients with AD as long as appropriate instruction and supervision is available. When considering the generalizability of our findings with regards to acceptability and safety of the intervention, it is important to be aware that the patients were highly selected, because patients with serious medical conditions and patients who were not motivated to exercise were not included. This was carried out to increase the likelihood of participants completing the intervention and to minimize safety issues for participants. All patients were able to follow instructions regarding the completion of the scales and tests, including Int J Geriatr Psychiatry 2014
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those who tested physical function. We observed neither ceiling nor floor effects in any of the tests applied in this study, except the SPPB. To avoid similar ceiling effects, more challenging functional performance tests should be implemented in future RCTs. The study was not designed to evaluate the effect of the exercise intervention. However, the postintervention decrease in heart rate at the same submaximal intensity during the 6-min bicycling prior to the graded exercise test indicate that endurance may have improved as a result of the intervention. The improvement may have been underestimated because of a too low intensity as indicated by the low HR level in three of the subjects (left panel, Figure 1). To avoid this, the initial intensity level needs to be increased. On the other hand, the borderline significant change in VO2peak may be because the increments in the graded test were too high (25 W every minute), resulting in inability to keep the cadence because of thigh muscle fatigue. Increments of 20 W every minute may be more appropriate in this patient group. The intervention was not expected to have any effect on hand grip strength in contrast to quadriceps strength and muscle power. The results regarding quadriceps strength and muscle power in the right leg may indicate a potential effect of the intervention. The lack of change in the left leg may be because two out of six participants reported knee pain in their left leg on the day of post-test (because of a fall and an overuse injury) In general, the intervention appeared to have a positive effect on the participants’ physical function, indicating that the training intensity, frequency, and duration were adequate.
The strengths of this study are that the experience of the participants and caregivers and their perception of the intervention were obtained through a focusgroup interview and a questionnaire. This enabled a qualitative study of patient and caregiver attitude towards the intervention. In our case, this methodology revealed important aspects relevant to all researchers planning a similar complex intervention in patients with dementia. This study has some limitations. The study was per design not powered to test effectiveness of the intervention. Our design did not enable assessments of certain important aspects of an RCT such as the randomization process because a control group was not included. In addition, the single-center design did not allow us to test how a multicenter setting will function. In conclusion, our findings support that it is feasible and safe to carry out a study of moderate-to-high intensity aerobic exercise in community-dwelling patients with mild to moderate AD. To reduce the risk of over use injury, extensive information about prevention of such injuries should be provided. Moreover, an adaptation period of more than 2 weeks with added emphasis on strength training appears advisable. Caregiver involvement, which is crucial for high attendance rates, should be supported, and structures to support caregivers in this role should be considered. Although patients in our study were able to use standard exercise equipment those with more advanced disease (e.g. as indicated by MMSE < 20) may need more supervision, and this should be considered in future studies. The use of a focus-group interview coupled with a questionnaire is useful for exploring
Figure 1 Heart during 6 min of bicycling and peak oxygen uptake.
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Feasibility study of exercise in AD
important issues related to feasibility. Finally, with regards to assessment of physical function, evidence of ceiling effects indicates that more challenging physical performance tests need to be implemented in this patient group. Conflict of interest None declared.
Key points Assessing the efficacy of non-pharmacological complex interventions such as aerobic exercise presents unique challenges, which requires careful assessment of feasibility. Moderate-to-high intensity aerobic exercise seems safe and feasible to apply in an interventional study in mild AD. To ensure a high rate of retention and participation, caregiver involvement is important. Studies testing other non-pharmacological complex interventions should consider including piloting with semi-quantitative interviews in the assessment of feasibility, because this may help uncover important aspects of a planned intervention.
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Acknowledgements This study was financially supported via a grant from the Danish Strategic Research Council as a part of the Preserving quality of life, physical health and functional ability in Alzheimer’s disease: the effect of physical exercise (ADEX) initiative. The project was partly supported with funds from the Association of Danish Physiotherapists, and the Faculty of Health Sciences, Copenhagen University. We would also like to cordially thank nurse Lis Christoffersen for conducting the focus-group interview with patients and caregivers. References Adlard P, Perreau VM, Pop V, Cotman CW. 2005. Voluntary exercise decreases amyloid load in a transgenic model of Alzheimer’s disease. J neurosci 25(17): 4217–4221.
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