Physical activity and enhanced fitness to improve cognitive function in older people without known cognitive impairment

 

Characteristics of included studies [ordered by study ID]

Bakken 2001

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Methods	Participants were not blinded. It is unclear whether the outcome assessor and care provider are blinded in this study. At randomisation 15 enrolled; 8 in the aerobic exercise group, 7 in the control group. Three participants were lost from the exercise condition, 2 were lost in the control group. No intention to treat analysis. Follow-up 8 weeks
Participants	10 participants (4 males, 6 females) in the age range of 72 to 91 years. Inclusion criteria: more than 65 years of age with no history of pulmonary disease, recurring falls, orthopaedic limitations or acute arthritis in the hands.
Interventions	Aerobic exercise: 1 hour sessions for 3 sessions per week for 8 consecutive weeks. 10 minutes of warming up, aerobic conditioning period that increased in duration and intensity (callisthenics, walking and cycling) systematically each week, 10 minutes of cooling down. Subjects heart rates did not exceed the upper limit of their THRR* Control: continued their normal everyday routine, which did not include any aerobic exercise according to the subjects report.
Outcomes	AI (Accuracy Index by finger tapping) Resting heart rate Resting systolic BP Resting rate-pressure product GXT test heart rate ** GXT test systolic BP GXT test RPP (Rate-Pressure product)
Notes	*THRR: (Karvonen) training HR = resting HR + [0.60-0.75 (HRR)]. HRR = age-predicted max HR - resting HR ** GXT: submaximal graded exercise tolerance test. Stage 1; stepping back and forth on the ground at a frequency of 20 mounts per minute for 3 minutes. Stage 2: stepping up and down a 10.16 cm high step. Stage 3: stepping up and down a 20.32 cm high step. Stage 4: stepping up and down a 30.48 cm high step. RPP; rate-pressure product = systolic BP multiplied by heart rate. A decrease in RPP is a quantitative measure of aerobic training.
Risk of bias
Item	Authors' judgement	Description
Allocation concealment?	Unclear	B - Unclear

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Blumenthal 1989 a

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Methods	101 participants (50 males and 51 females) were randomised either to aerobic exercise (N = 33), yoga/flexibility (N = 34) or control (N = 34). Two participants were lost from both the aerobic group and the control group. No intention to treat analysis. Patients were not blinded, it is unclear whether the care provider and the outcome assessor were blinded. Follow up: 16 weeks
Participants	Participants (only the 51 females) aged 60 to 83 years Inclusion criteria: free from clinical manifestations of coronary disease assessed by medical history, physical examination, bicycle ergometry exercise testing. Exclusion criteria: positive ECG during exercise testing, evidence of coronary artery disease, asthma, pulmonectomy, uncontrolled hypertension, beta-blocker therapy.
Interventions	Aerobic exercise: 3 supervised sessions for 16 weeks. Training based on 70% of max heart rate achieved on exercise test. 10 minutes of warming up, 30 minutes of bicycle ergometry, 15 minutes of brisk walking/jogging and arm ergometry, 5 minutes of cooling down. Yoga/flexibility: 2 supervised sessions a week for 60 minutes over 16 weeks. Controls: not to change their physical activity habits and especially not to engage in any aerobic exercise for the studyperiod.
Outcomes	Tapping (dominant/non-dominant) Digit span (forward / backward) Benton Revised Visual Retention test (correct/error) Story Recall of the Randt Memory test (immediate) - data on the delayed Story Recall of the Randt Memory test could not be traced by the authors. Selective reminding test (total/intrusions) Trail making (part B) Digit Symbol substitution 2 & 7 test (digits/letters) Stroop colour word Stroop interference Verbal fluency Non-verbal fluency VO2 max AT
Notes
Risk of bias
Item	Authors' judgement	Description
Allocation concealment?	Unclear	B - Unclear

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Blumenthal 1989 b

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Methods	Details in Blumenthal 1989 a
Participants	Participants: only the 50 males Details in Blumenthal 1989 a
Interventions	Details in Blumenthal 1989 a
Outcomes	Details in Blumenthal 1989 a
Notes
Risk of bias
Item	Authors' judgement	Description
Allocation concealment?	Unclear	B - Unclear

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Emery 1990 a

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Methods	48 subjects (8 males and 40 females) were randomly assigned to an aerobic exercise programme (N = 15), social activity group (N = 15) or a control group (N = 18). One subject was lost from the aerobic group, 4 from the social group and 4 from the control group. No intention to treat analysis. The participants were not blinded, it is unclear whether the outcome assessor and the caregiver were blinded. Follow-up: 12 weeks
Participants	48 participants aged 61 to 86 years. Inclusion criteria not described. Exclusion criteria not described.
Interventions	Exercise: 3 sessions per week for approximately 60 minutes. 10 to 15 minutes of stretching exercises followed by 20 to 25 minutes of aerobic exercise (at 70% of age-adjusted max = 220-age), including rapid walking as well as rhythmic muscle strengthening exercises (e.g. repeatedly standing up and sitting down). 5 minutes of cooling down with dancing and light exercises. Social activity: 3 sessions per week for 60 minutes. Participation in non-physical activities (card games, art projects, political discussion groups, watching films). Controls: not described.
Outcomes	Digit Symbol substitution Digit Span Copying Words Copying Numbers (digit/sec) Weight (kg) Resting HR Resting blood pressure (syst/diast) BP during modified step test HR during modified step test Sit-and-reach test
Notes
Risk of bias
Item	Authors' judgement	Description
Allocation concealment?	Unclear	B - Unclear

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Emery 1998

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Methods	Randomisation procedure: taken from a random number schedule. Participants were informed of their group assignment given by sealed envelopes after baseline testing. 79 participants (37 males and 42 females) were randomised: 29 in the aerobic exercise group, both 25 in the education group and control group. Four subjects were lost from the exercise condition, 2 from the education programme. Intention to treat was not performed. Patients were not blinded, whether the care provider and the assessors were blinded is unclear. Follow-up: 10 weeks.
Participants	79 COPD patients of the age of 66.6 ± 6.5 enrolled. Inclusion criteria: aged over 50, FEV1 / FVC < .70 and clinical symptoms of COPD for more than 6 months. Exclusion criteria: significant cardiac disease during the previous 3 months or other medical conditions that would affect exercise tolerance or learning skills. Primarily acute, reversible airway disease (asthma) without fixed airflow obstruction. Tuberculosis, pulmonary fibrosis, cancer.
Interventions	Exercise, education and stress management (EXESM): daily sessions for 4 hours a day during the initial 5-week period. 45 minutes of aerobic exercise as well as strength training on Nautilus equipment. 10 minutes of warming up, 35 minutes of aerobic exercise (cycling, arm ergometry, walking) and cooling down. Educational lectures on topics relevant for COPD patients. Weekly a 1 hour group meeting for stress management and psychological support. Following the first 5 weeks, EXESM participants followed a program of 3 sessions a week with 60 to 90 min of exercise and 1 hour a week of stress management. Thus, 37 exercise sessions, 16 educational sessions and 10 stress management classes in 10 weeks. Education and stress management (ESM): 16 educational sessions and 10 stress management classes in 10 weeks. Control: not to alter their physical activities during the study.
Outcomes	Digit vigilance test Finger tapping Trailmaking (part A and B) Digit symbol substitution Verbal fluency VO2 max HR max Workload max
Notes
Risk of bias
Item	Authors' judgement	Description
Allocation concealment?	Yes	A - Adequate

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Fabre 2002

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Methods	32 participants (5 males and 27 females) at randomisation; each group (physical training, memory training, combined physical/memory training and controls) contained 8 subjects. All the participants completed the study and intention to treat analysis was not necessary. Patients were not blinded, it is unclear whether the assessor and the care provider were blinded. Follow-up: 2 months
Participants	32 participants in the age range of 60 to 76 years. Inclusion criteria are not described. Exclusion criteria: positive ECG during exercise testing, present depression, could not breathe through the tube during exercise testing, various other reasons such as disease during training.
Interventions	Physical training: two supervised 1 hour exercise sessions per week for 2 months: walking and running to maintain target heart rate (target heart rate corresponded to the ventilatory threshold). 5 minutes of warming up, 45 minutes of walking/running, 10 minutes of cooling down. Memory training: 90 minutes of sessions once a week for 8 weeks. 15 minutes of explaining, Israel's method in core. Combined physical training and memory training. Controls; no training whatsoever.
Outcomes	Memory quotient (= total score of al WAIS subtests) Paired associates learning Digit span forward Logical memory immediate recall Orientation General information Mental control Visual reproductions VO2 max VO2 max at Vth Max O2 pulse Max O2 pulse at Vth
Notes
Risk of bias
Item	Authors' judgement	Description
Allocation concealment?	Unclear	B - Unclear

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Hassmén 1997 a

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Methods	40 participants (20 males and 20 females) were matched in pairs (according to sex, age, cognitive results and heart rate response) and one of each pair was randomly assigned to the exercise group. 20 participants per group, no one was lost to follow-up and intention to treat was not necessary. Patients were not blinded, it is unclear whether the outcome assessor and the care provider were blinded. Follow-up: 3 months
Participants	20 female participants, aged 55 to 75 years. Inclusion criteria: free from medical conditions or impairment (according to self-ratings) and did not use medication in the past six months. Furthermore, the participants were sedentary (did not take part in any form of regular physical exercise).
Interventions	Exercise group: regular walking exercise 3 times a week during three months with intensities according to RPEs (Borg scale) of 9 (very light), 11 (fairly light) and 13 (somewhat hard). The performed exercise gave rise to heart rate responses of 95 to 125 beats/min. Control group: the members were given home assignments to be performed 3 times per week.
Outcomes	Simple RT (min) Choice RT (min) Immediate recall Delayed Recall Face recognition Digit Span Heart rate (beats/min) RPE
Notes
Risk of bias
Item	Authors' judgement	Description
Allocation concealment?	Unclear	B - Unclear

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Hassmén 1997 b

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Methods	Details in Hassmén 1997 a
Participants	20 male participants Details in Hassmén 1997 a
Interventions	Details in Hassmén 1997 a
Outcomes	Details in Hassmén 1997 a
Notes
Risk of bias
Item	Authors' judgement	Description
Allocation concealment?	Unclear	B - Unclear

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Kramer 2001

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Methods	174 participants at randomisation. Subsequently 50 subjects were dropped from the study because of withdrawal from the training protocol or incomplete data. The study was completed by 124 individuals; 58 (13 men) in the aerobic group and 66 (20 men) in the stretching and toning group. No Intention to treat analysis. Participants were not blinded, it is unclear whether the care provider and the assessor were blinded. Follow-up period: 6 months.
Participants	124 participants aged 60 to 75 years of age. Inclusion criteria: aged 60 to 75 years, sedentary (no physical activity in the preceeding 6 months), capable of performing exercise, physicians examination and consent to participate, successful completion of graded exercise test without evidence of cardiac abnormalities, initial depression score on the GDS below clinical level, no history of neurologic disorders, corrected (near & far) acuity of 20/40 or better, fewer than three errors on the Pfeiffer Mental Status questionnaire. Exclusion criteria: younger than 60 years, self-reported activity on a regular basis (2 times a week) in the preceeding 6 months, any physical disability that prohibits mobility, non-consent of physician, evidence of abnormal cardiac responses during graded exercise testing, depression score on the GDS indicative of clinical depression, history of neurologic disorders, corrected (near & far) acuity greater than 20/40, more than three errors on the Pfeiffer questionnaire.
Interventions	Aerobic walking exercise: 3 supervised sessions per week for 6 months. Warming up, 40 minutes of brisk walking (gradually beginning at 10 to 15 minutes up to 40 minutes), cooling down. Initial exercise was performed at 50 to 55% of VO2 max and increased to 65 to 70% of VO2 max. Stretching and toning: 3 times a week supervised sessions for 6 months. The program emphasized stretches for all the large muscle group of the upper and lower extremities. Each stretch was held for 20 to 30 seconds and repeated 5 to 10 times. Each session was preceeded and followed by 10 minutes of warm-up and cooling down.
Outcomes	Visual search task Response compatibility task Task switching paradigm Stopping paradigm Spatial attention task Rey auditory verbal learning test Pursuit rotor task Self-ordered pointing task Spatial working memory Verbal working memory Face recognition task Digit-digit and digit-symbol tests Forward and backward digit span VO2 max (ml/kg/min) Time on treadmill (min) Rockport 1-mile walk (min)
Notes
Risk of bias
Item	Authors' judgement	Description
Allocation concealment?	Unclear	B - Unclear

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Madden 1989

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Methods	85 participants (44 males and 41 females) at randomisation; 28 in the aerobic group, 30 in the yoga group and 27 served as controls. Three participants were lost from the exercise group, 2 from the yoga group and 1 from the controls. No intention to treat analysis. Participants were not blinded, it is unclear whether the care provider and the assessor are blinded. Follow-up: 16 weeks.
Participants	Participants were 60 to 83 years of age. Inclusion criteria: free of medical conditions that would preclude a programme of either aerobic exercise or yoga Exclusion criteria: uncontrolled hypertension, diabetes, or coronary heart disaese, use of beta-blockers or psychotropic medication.
Interventions	Aerobic exercise: 3 supervised sessions per week for 16 weeks. 10 minutes of warming up, 30 minutes of cycling, 15 minutes of brisk walking and/or jogging, 5 minutes of cooling down. All exercise was performed in target (training) heart range (70% of max during initial exercise test). Yoga: 2 a week 60 minutes supervised yoga sessions for 16 weeks. Control: no change to their physical activity habits for the length of the study.
Outcomes	Letter search RT task (short-term memory) Word comparison RT task (long-term memory) VO2 max
Notes
Risk of bias
Item	Authors' judgement	Description
Allocation concealment?	Unclear	B - Unclear

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Moul 1995

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Methods	30 participants (11 males, 19 females), the walking, weight training and control group all contained 10 participants. Participants were not blinded; it is unclear whether the outcome assessor and the caregiver were blinded. No participants were lost to follow-up, intention to treat analysis was not necessary. Follow-up: 16 weeks.
Participants	30 participants aged 65 to 72 years. Inclusion criteria: nondiseased (no current symptoms or signs suggestive of heart disease), nonactive (defined as < 2 moderate to vigorous aerobic or resistance training sessions of > 20 minutes per week).
Interventions	Walking: 5 sessions per week. Walking 30 minutes at 60% of HRR (as determined by treadmill testing). Walking duration was increased 2 minutes per week until they reached 40 minutes and HRR were adjusted after 8 weeks of training to 65% of HRR. Weight training: 5 sessions per week of upper and lower body exercises on alternate days of the week. Abdominal crunches and back extensions were performed in each session. Weight group employed a daily adjusted progressive resistive exercise programme (DAPRE) using weights. Controls: 5 sessions per week mild stretching exercises for 30 to 40 minutes. Minimal challenge to the cardiovascular or muscular systems.
Outcomes	Immediate Memory (Ross Information Processing Assessment) Recent Memory (RIPA) Temporal Orientation (RIPA) Problem Solving and abstract reasoning (RIPA) Organization (RIPA) Auditory Processing (RIPA) Weight (kg) Sum of seven skinfolds (mm) VO2 max (ml/kg/min) Time on treadmill (min) Ventilation (ml/min) RER Knee extension (lb) Elbow flexion (lb)
Notes
Risk of bias
Item	Authors' judgement	Description
Allocation concealment?	Unclear	B - Unclear

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Panton 1990

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Methods	57 participants were randomised in a walk/jog group, a strength group and a control group. Eight participants were lost to follow-up; it is unclear from which condition these subjects were lost. Intention to treat analysis was not performed. Analyses were performed on 17 participants in the walk/jog group, 20 subjects in the strength group and 12 controls. Participants were not blinded; it is unclear whether the outcome assessor and the caregiver were blinded. Follow-up: 26 weeks.
Participants	Participants were retired professionals from the university community of Gainesville, FL and 70 to 79 years of age. Inclusion criteria: sedentary non-smokers who had no contraindications to exercise testing or training. Free of any overt evidence of coronary artery disease and other conditions that would limit their participation in a vigorous exercise programme (as tested with a diagnostic graded exercise test (using a modified Naughton protocol). Exclusion criteria werer not described.
Interventions	The walk/jog group participated in three exercise sessions per week for the duration of the study. All training sessions were preceded by 5 to 10 minutes of stretching and warm-up and ended with 5 min of cool-down exercises. Initially, participants started walking/jogging for 20 minutes at 50% of their maximal heart rate reserve (HRRmax). The duration was increased by 5 min every 2 weeks until the subjects walked for 40 minutes. Training intensity was gradually increased until subjects could walk at 60 to 70% of their HRRmax. During the 14th week of training exercise intensity was further increased by alternating fast walk/moderate walk or fast walk/slow jog intervals. Five participants increased their training intensity by increasing the slope of the treadmill. By the 26th week of training, all subjects performed at 85% of HRRmax for 35 to 45 min. Subjects in the strength group participated in 30 min sessions, 3 times a week for 26 weeks. Workouts consisted of one set of 10 variable resistance Nautilus exercises (leg, arm and torso muscles). During the first 13 weeks, subjects used light to moderate weights and performed 8 to 12 repetitions for each exercise. During the last 13 weeks, resistance was increased substantially and subjects were encouraged to train to volitional muscular fatigue. When subjects could complete 12 or more repetitions, the resistance was increased. Participants in the control group were asked not to change their lifestyle over the 6 month duration of the study.
Outcomes	Total simple Reaction time Fractionated Reaction time (PreMotorTime and MotorTime) Speed of Movement measurements Fat percentage (predicted from body density) Body density (7 skinfolds) 1RM muscle strength test VO2max
Notes
Risk of bias
Item	Authors' judgement	Description
Allocation concealment?	Unclear	B - Unclear

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Whitehurst 1991

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Methods	14 participants at randomisation (all females): 7 in both the exercise and the control group. All the subjects completed the study, intention to treat analysis was not necessary. Participants were not blinded, it is unclear whether the care provider and the assessor were blinded. Follow-up: 8 weeks.
Participants	Females in the age range of 61 to 73 years. Inclusion criteria: did not participate in aerobic exercise more than one time per week prior to the study. Medical clearance from a physician (resting ECG and physical examination). Free of primary cardiovascular risk factors. Maintained the household.
Interventions	Exercise: 3 supervised sessions per week for 8 weeks (total of 24 sessions). 5 to 10 minutes of warming up and cooling down. The subjects cycled for 8 to 10 minutes the first week to provide acclimatization. Thereafter, 3 to 5 minutes was added to subsequent sessions so that by week 4 all subjects were cycling for 35 to 40 minutes at their target heart rate. Control: did not engage in any form of vigorous physical activity during the course of the study.
Outcomes	Simple reaction time Choice reaction time Estimated VO2 max
Notes
Risk of bias
Item	Authors' judgement	Description
Allocation concealment?	Unclear	B - Unclear

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Characteristics of excluded studies [ordered by study ID]

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Study	Reason for exclusion
Barry 1966	Not RCT but CCT.
Blumenthal 1988	Participants were to young to meet the given inclusion criteria of this review.
Blumenthal 1991	Data were already published in Blumenthal 1989.
Dietrich 2004	Data could not test the cardiovascular fitness hypothesis since cognition was assessed during exercise.
Dustman 1984	No RCT but quasi-randomised study (participants "alternately assigned").
Emery 1990 b	Perceived (subjective) measurements of cognition were analysed according to groups but the objective measures of cognition were analysed according to perceived measures of cognition.
Emery 2003	Within subjects repeated measures design to evaluate the influence of music and exercise on cognition. No control group.
Etnier 1997 a	No exercise intervention.
Etnier 2001	The control group was encouraged to continue exercising; however no formal program was provided.
Fabre 1999	No means and SDs for cognitive data. These results are described in Fabre2001.
Hassmén 1992	No RCT but 'matched controls'.
Hawkins 1992	No fitness parameter present.
Hill 1993	No RCT but quasi-randomised study (participants "assigned to intervention group").
Kerschan 2002	Both groups followed aerobic training intervention.
Kharti 2001	Study participants were depressed older men and women: depression was an exclusion criterion for our review.
Kramer 1999	This article provides no quantitative data on which an analysis can be based. Quantitative data of the RCT of this research group is provided in Kramer 2001, which is included in our review.
Molloy 1988	Exercise was not intended to improve aerobic fitness.
Oken 2004	Participants were too young to meet the given inclusion criteria of this review.
Okumiya 1996	No fitness parameter present.
Palleschi 1996	Participants were elderly patients with senile dementia of the Alzheimer type: this was an exclusion criterion for our review.
Perri 1984	Not a true RCT but a clinical trial
Pierce 1993	Participants were too young to meet the given inclusion criteria of this review.
Powell 1974	Narrative review; this article provides no quantitative data.
Rikli 1991	Balance, sit and reach flexibility, shoulder flexibility, and grip strength were given as fitness parameters. We did not include this RCT since neither of the two fitness parameters reflect aerobic fitness.
Stevenson 1990	Both intervention groups recieved aerobic training (different levels of intensity).
Wallman 2004	Participants were too young to meet the given inclusion criteria of this review.
Wilbur 2005	No objective measures of cognitive parameters (symptom impact inventory).
Williams 1997	No objective measures of fitness, only subjective measures (Percieved General Fitness).

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Comparison 1. Aerobic exercise vs. any intervention

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Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

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 1 Cognitive speed

6

312

Std. Mean Difference (IV, Random, 95% CI)

0.24 [0.01, 0.46]

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1.1 Simple reaction time

1

37

Std. Mean Difference (IV, Random, 95% CI)

-0.10 [-0.75, 0.54]

---

1.2 Choice reaction time

0

0

Std. Mean Difference (IV, Random, 95% CI)

Not estimable

---

1.3 Trailmaking part A

1

48

Std. Mean Difference (IV, Random, 95% CI)

0.52 [-0.06, 1.10]

---

1.4 Digit symbol substitution

4

227

Std. Mean Difference (IV, Random, 95% CI)

0.23 [-0.03, 0.50]

---

 2 Verbal memory functions (immediate)

4

209

Std. Mean Difference (IV, Random, 95% CI)

0.17 [-0.10, 0.44]

---

2.1 Randt Memory test story recall

2

65

Std. Mean Difference (IV, Random, 95% CI)

0.33 [-0.16, 0.82]

---

2.2 16 words immediate recall

0

0

Std. Mean Difference (IV, Random, 95% CI)

Not estimable

---

2.3 Ross Information Processing Assessment immediate memory

1

20

Std. Mean Difference (IV, Random, 95% CI)

0.06 [-0.82, 0.93]

---

2.4 Wechsler Adult Intelligence Scales logical memory immediate recall

0

0

Std. Mean Difference (IV, Random, 95% CI)

Not estimable

---

2.5 Rey auditory verbal learning trial I-V

1

124

Std. Mean Difference (IV, Random, 95% CI)

0.10 [-0.25, 0.45]

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 3 Visual memory functions (immediate)

2

65

Mean Difference (IV, Fixed, 95% CI)

0.04 [-1.66, 1.75]

---

3.1 Benton visual retention (#error)

2

65

Mean Difference (IV, Fixed, 95% CI)

0.04 [-1.66, 1.75]

---

3.2 Wechsler Memory Scales visual reproduction

0

0

Mean Difference (IV, Fixed, 95% CI)

Not estimable

---

 4 Working memory

3

189

Mean Difference (IV, Random, 95% CI)

0.36 [-0.31, 1.03]

---

4.1 Digit span backward

3

189

Mean Difference (IV, Random, 95% CI)

0.36 [-0.31, 1.03]

---

 5 Memory functions (delayed)

1

124

Mean Difference (IV, Fixed, 95% CI)

0.5 [-0.44, 1.44]

---

5.1 16 words delayed recall

0

0

Mean Difference (IV, Fixed, 95% CI)

Not estimable

---

5.2 Rey auditory verbal learning delayed recall trial

1

124

Mean Difference (IV, Fixed, 95% CI)

0.5 [-0.44, 1.44]

---

 6 Executive functions

7

326

Std. Mean Difference (IV, Random, 95% CI)

0.16 [-0.20, 0.51]

---

6.1 Trailmaking part B

2

65

Std. Mean Difference (IV, Random, 95% CI)

0.35 [-0.14, 0.85]

---

6.2 Ross Information Processing Assessment problem solving and abstract reasoning

1

20

Std. Mean Difference (IV, Random, 95% CI)

-0.88 [-1.81, 0.05]

---

6.3 Wechsler Memory Scales mental control

1

16

Std. Mean Difference (IV, Random, 95% CI)

-0.44 [-1.44, 0.55]

---

6.4 Word comparison (#error)

1

53

Std. Mean Difference (IV, Random, 95% CI)

0.24 [-0.30, 0.78]

---

6.5 Task switching paradigm (accuracy)

1

124

Std. Mean Difference (IV, Random, 95% CI)

0.03 [-0.32, 0.38]

---

6.6 Verbal fluency

1

48

Std. Mean Difference (IV, Random, 95% CI)

0.87 [0.28, 1.47]

---

 7 Perception

3

160

Std. Mean Difference (IV, Random, 95% CI)

-0.10 [-0.63, 0.43]

---

7.1 Face recognition (delayed recall)

1

124

Std. Mean Difference (IV, Random, 95% CI)

0.17 [-0.18, 0.53]

---

7.2 Ross Information Processing Assessment auditory processing

1

20

Std. Mean Difference (IV, Random, 95% CI)

-0.17 [-1.05, 0.71]

---

7.3 Wechsler Adult Intelligence Scales visual reproduction

1

16

Std. Mean Difference (IV, Random, 95% CI)

-0.81 [-1.84, 0.22]

---

 8 Cognitive inhibition

3

189

Std. Mean Difference (IV, Random, 95% CI)

-0.02 [-0.31, 0.26]

---

8.1 Stroop color word (interference)

2

65

Std. Mean Difference (IV, Random, 95% CI)

-0.07 [-0.56, 0.42]

---

8.2 Stopping task (accuracy choice RT)

1

124

Std. Mean Difference (IV, Random, 95% CI)

0.01 [-0.35, 0.36]

---

 9 Visual attention

5

290

Std. Mean Difference (IV, Random, 95% CI)

0.26 [0.02, 0.49]

---

9.1 Digit vigilance

1

48

Std. Mean Difference (IV, Random, 95% CI)

0.45 [-0.13, 1.02]

---

9.2 Tracking (accuracy index)

0

0

Std. Mean Difference (IV, Random, 95% CI)

Not estimable

---

9.3 2&7 test

2

65

Std. Mean Difference (IV, Random, 95% CI)

0.30 [-0.19, 0.79]

---

9.4 Letter search primary task RT

1

53

Std. Mean Difference (IV, Random, 95% CI)

0.05 [-0.49, 0.59]

---

9.5 Visual search (accuracy)

1

124

Std. Mean Difference (IV, Random, 95% CI)

0.25 [-0.10, 0.60]

---

 10 Auditory attention

5

243

Mean Difference (IV, Random, 95% CI)

0.05 [-0.45, 0.54]

---

10.1 Digit span forward

5

243

Mean Difference (IV, Random, 95% CI)

0.05 [-0.45, 0.54]

---

 11 Motor function

4

237

Std. Mean Difference (IV, Random, 95% CI)

0.52 [-0.25, 1.30]

---

11.1 Finger tapping

3

113

Std. Mean Difference (IV, Random, 95% CI)

0.72 [-0.35, 1.78]

---

11.2 Pursuit rotor task (tracking error)

1

124

Std. Mean Difference (IV, Random, 95% CI)

0.02 [-0.33, 0.38]

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Comparison 2. Aerobic exercise vs. no intervention

---

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

---

 1 Cognitive speed

8

236

Std. Mean Difference (IV, Random, 95% CI)

0.10 [-0.16, 0.36]

---

1.1 Simple reaction time

1

29

Std. Mean Difference (IV, Random, 95% CI)

0.02 [-0.71, 0.76]

---

1.2 Choice reaction time

3

54

Std. Mean Difference (IV, Random, 95% CI)

-0.38 [-0.93, 0.16]

---

1.3 Trailmaking part A

1

50

Std. Mean Difference (IV, Random, 95% CI)

0.08 [-0.47, 0.64]

---

1.4 Digit symbol substitution

3

103

Std. Mean Difference (IV, Random, 95% CI)

0.38 [-0.02, 0.78]

---

 2 Verbal memory functions (immediate)

6

141

Std. Mean Difference (IV, Random, 95% CI)

0.06 [-0.30, 0.42]

---

2.1 Randt Memory test story recall

2

65

Std. Mean Difference (IV, Random, 95% CI)

-0.05 [-0.54, 0.44]

---

2.2 16 words immediate recall

2

40

Std. Mean Difference (IV, Random, 95% CI)

-0.11 [-0.73, 0.51]

---

2.3 Ross Information Processing Assessment immediate memory

1

20

Std. Mean Difference (IV, Random, 95% CI)

1.14 [0.18, 2.10]

---

2.4 Wechsler Adult Intelligence Scales logical memory immediate recall

1

16

Std. Mean Difference (IV, Random, 95% CI)

-0.22 [-1.21, 0.76]

---

2.5 Rey auditory verbal learning trial I-V

0

0

Std. Mean Difference (IV, Random, 95% CI)

Not estimable

---

 3 Visual memory functions (immediate)

3

81

Std. Mean Difference (IV, Random, 95% CI)

-0.15 [-0.58, 0.29]

---

3.1 Benton visual retention (#error)

2

65

Std. Mean Difference (IV, Random, 95% CI)

-0.07 [-0.56, 0.42]

---

3.2 Wechsler Memory Scales visual reproduction

1

16

Std. Mean Difference (IV, Random, 95% CI)

-0.46 [-1.45, 0.54]

---

 4 Working memory

2

65

Mean Difference (IV, Fixed, 95% CI)

0.49 [-0.76, 1.73]

---

4.1 Digit span backward

2

65

Mean Difference (IV, Fixed, 95% CI)

0.49 [-0.76, 1.73]

---

 5 Memory functions (delayed)

2

40

Mean Difference (IV, Fixed, 95% CI)

-0.55 [-2.11, 1.00]

---

5.1 16 words delayed recall

2

40

Mean Difference (IV, Fixed, 95% CI)

-0.55 [-2.11, 1.00]

---

5.2 Rey auditory verbal learning delayed recall trial

0

0

Mean Difference (IV, Fixed, 95% CI)

Not estimable

---

 6 Executive functions

6

202

Std. Mean Difference (IV, Random, 95% CI)

0.23 [-0.09, 0.56]

---

6.1 Trailmaking part B

2

65

Std. Mean Difference (IV, Random, 95% CI)

0.04 [-0.45, 0.53]

---

6.2 Ross Information Processing Assessment problem solving and abstract reasoning

1

20

Std. Mean Difference (IV, Random, 95% CI)

1.08 [0.13, 2.03]

---

6.3 Wechsler Memory Scales mental control

1

16

Std. Mean Difference (IV, Random, 95% CI)

-0.19 [-1.17, 0.79]

---

6.4 Word comparison (#error)

1

51

Std. Mean Difference (IV, Random, 95% CI)

0.05 [-0.50, 0.60]

---

6.5 Task switching paradigm (accuracy)

0

0

Std. Mean Difference (IV, Random, 95% CI)

Not estimable

---

6.6 Verbal fluency

1

50

Std. Mean Difference (IV, Random, 95% CI)

0.51 [-0.06, 1.07]

---

 7 Perception

4

76

Std. Mean Difference (IV, Random, 95% CI)

0.10 [-0.38, 0.57]

---

7.1 Face recognition (delayed recall)

2

40

Std. Mean Difference (IV, Random, 95% CI)

0.13 [-0.60, 0.86]

---

7.2 Ross Information Processing Assessment auditory processing

1

20

Std. Mean Difference (IV, Random, 95% CI)

0.48 [-0.41, 1.38]

---

7.3 Wechsler Adult Intelligence Scales visual reproduction

1

16

Std. Mean Difference (IV, Random, 95% CI)

-0.46 [-1.45, 0.54]

---

 8 Cognitive inhibition

2

65

Mean Difference (IV, Fixed, 95% CI)

2.47 [-0.62, 5.55]

---

8.1 Stroop color word (interference)

2

65

Mean Difference (IV, Fixed, 95% CI)

2.47 [-0.62, 5.55]

---

8.2 Stopping task (accuracy choice RT)

0

0

Mean Difference (IV, Fixed, 95% CI)

Not estimable

---

 9 Visual attention

5

176

Std. Mean Difference (IV, Random, 95% CI)

0.09 [-0.20, 0.39]

---

9.1 Digit vigilance

1

50

Std. Mean Difference (IV, Random, 95% CI)

-0.08 [-0.64, 0.47]

---

9.2 Tracking (accuracy index)

1

10

Std. Mean Difference (IV, Random, 95% CI)

0.76 [-0.55, 2.07]

---

9.3 2&7 test

2

65

Std. Mean Difference (IV, Random, 95% CI)

0.04 [-0.45, 0.52]

---

9.4 Letter search primary task RT

1

51

Std. Mean Difference (IV, Random, 95% CI)

0.23 [-0.32, 0.78]

---

9.5 Visual search (accuracy)

0

0

Std. Mean Difference (IV, Random, 95% CI)

Not estimable

---

 10 Auditory attention

5

121

Mean Difference (IV, Random, 95% CI)

0.52 [0.13, 0.91]

---

10.1 Digit span forward

5

121

Mean Difference (IV, Random, 95% CI)

0.52 [0.13, 0.91]

---

 11 Motor function

3

115

Mean Difference (IV, Random, 95% CI)

1.17 [0.19, 2.15]

---

11.1 Finger tapping

3

115

Mean Difference (IV, Random, 95% CI)

1.17 [0.19, 2.15]

---

11.2 Pursuit rotor task (tracking error)

0

0

Mean Difference (IV, Random, 95% CI)

Not estimable

---

 

Comparison 3. Aerobic exercise vs. flexibility / balance programme

---

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

---

 1 Cognitive speed

3

189

Mean Difference (IV, Random, 95% CI)

1.29 [-0.41, 2.98]

---

1.1 Simple reaction time

0

0

Mean Difference (IV, Random, 95% CI)

Not estimable

---

1.2 Choice reaction time

0

0

Mean Difference (IV, Random, 95% CI)

Not estimable

---

1.3 Trailmaking part A

0

0

Mean Difference (IV, Random, 95% CI)

Not estimable

---

1.4 Digit symbol substitution

3

189

Mean Difference (IV, Random, 95% CI)

1.29 [-0.41, 2.98]

---

 2 Verbal memory functions (immediate)

3

189

Std. Mean Difference (IV, Random, 95% CI)

0.18 [-0.11, 0.47]

---

2.1 Randt Memory test story recall

2

65

Std. Mean Difference (IV, Random, 95% CI)

0.33 [-0.16, 0.82]

---

2.2 16 words immediate recall

0

0

Std. Mean Difference (IV, Random, 95% CI)

Not estimable

---

2.3 Ross Information Processing Assessment immediate memory

0

0

Std. Mean Difference (IV, Random, 95% CI)

Not estimable

---

2.4 Wechsler Adult Intelligence Scales logical memory immediate recall

0

0

Std. Mean Difference (IV, Random, 95% CI)

Not estimable

---

2.5 Rey auditory verbal learning trial I-V

1

124

Std. Mean Difference (IV, Random, 95% CI)

0.10 [-0.25, 0.45]

---

 3 Visual memory functions (immediate)

2

65

Mean Difference (IV, Fixed, 95% CI)

0.04 [-1.66, 1.75]

---

3.1 Benton visual retention (#error)

2

65

Mean Difference (IV, Fixed, 95% CI)

0.04 [-1.66, 1.75]

---

3.2 Wechsler Memory Scales visual reproduction

0

0

Mean Difference (IV, Fixed, 95% CI)

Not estimable

---

 4 Working memory

3

189

Mean Difference (IV, Random, 95% CI)

0.36 [-0.31, 1.03]

---

4.1 Digit span backward

3

189

Mean Difference (IV, Random, 95% CI)

0.36 [-0.31, 1.03]

---

 5 Memory functions (delayed)

1

124

Mean Difference (IV, Fixed, 95% CI)

0.5 [-0.44, 1.44]

---

5.1 16 words delayed recall

0

0

Mean Difference (IV, Fixed, 95% CI)

Not estimable

---

5.2 Rey auditory verbal learning delayed recall trial

1

124

Mean Difference (IV, Fixed, 95% CI)

0.5 [-0.44, 1.44]

---

 6 Executive functions

4

242

Std. Mean Difference (IV, Random, 95% CI)

0.16 [-0.09, 0.41]

---

6.1 Trailmaking part B

2

65

Std. Mean Difference (IV, Random, 95% CI)

0.35 [-0.14, 0.85]

---

6.2 Ross Information Processing Assessment problem solving and abstract reasoning

0

0

Std. Mean Difference (IV, Random, 95% CI)

Not estimable

---

6.3 Wechsler Memory Scales mental control

0

0

Std. Mean Difference (IV, Random, 95% CI)

Not estimable

---

6.4 Word comparison (#error)

1

53

Std. Mean Difference (IV, Random, 95% CI)

0.24 [-0.30, 0.78]

---

6.5 Task switching paradigm (accuracy)

1

124

Std. Mean Difference (IV, Random, 95% CI)

0.03 [-0.32, 0.38]

---

6.6 Verbal fluency

0

0

Std. Mean Difference (IV, Random, 95% CI)

Not estimable

---

 7 Perception

1

124

Mean Difference (IV, Fixed, 95% CI)

3.70 [-3.68, 11.08]

---

7.1 Face recognition (delayed recall)

1

124

Mean Difference (IV, Fixed, 95% CI)

3.70 [-3.68, 11.08]

---

7.2 Ross Information Processing Assessment auditory processing

0

0

Mean Difference (IV, Fixed, 95% CI)

Not estimable

---

7.3 Wechsler Adult Intelligence Scales visual reproduction

0

0

Mean Difference (IV, Fixed, 95% CI)

Not estimable

---

 8 Cognitive inhibition

3

189

Std. Mean Difference (IV, Random, 95% CI)

-0.02 [-0.31, 0.26]

---

8.1 Stroop color word (interference)

2

65

Std. Mean Difference (IV, Random, 95% CI)

-0.07 [-0.56, 0.42]

---

8.2 Stopping task (accuracy choice RT)

1

124

Std. Mean Difference (IV, Random, 95% CI)

0.01 [-0.35, 0.36]

---

 9 Visual attention

4

242

Std. Mean Difference (IV, Random, 95% CI)

0.22 [-0.03, 0.47]

---

9.1 Digit vigilance

0

0

Std. Mean Difference (IV, Random, 95% CI)

Not estimable

---

9.2 Tracking (accuracy index)

0

0

Std. Mean Difference (IV, Random, 95% CI)

Not estimable

---

9.3 2&7 test

2

65

Std. Mean Difference (IV, Random, 95% CI)

0.30 [-0.19, 0.79]

---

9.4 Letter search primary task RT

1

53

Std. Mean Difference (IV, Random, 95% CI)

0.05 [-0.49, 0.59]

---

9.5 Visual search (accuracy)

1

124

Std. Mean Difference (IV, Random, 95% CI)

0.25 [-0.10, 0.60]

---

 10 Auditory attention

3

189

Mean Difference (IV, Random, 95% CI)

-0.20 [-0.81, 0.40]

---

10.1 Digit span forward

3

189

Mean Difference (IV, Random, 95% CI)

-0.20 [-0.81, 0.40]

---

 11 Motor function

3

189

Std. Mean Difference (IV, Random, 95% CI)

0.07 [-0.21, 0.36]

---

11.1 Finger tapping

2

65

Std. Mean Difference (IV, Random, 95% CI)

0.17 [-0.31, 0.66]

---

11.2 Pursuit rotor task (tracking error)

1

124

Std. Mean Difference (IV, Random, 95% CI)

0.02 [-0.33, 0.38]

---

 

Comparison 4. Aerobic exercise vs. strength programme

---

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

---

 1 Verbal memory functions (immediate)

1

20

Mean Difference (IV, Fixed, 95% CI)

0.30 [-4.17, 4.77]

---

1.1 Randt Memory test story recall

0

0

Mean Difference (IV, Fixed, 95% CI)

Not estimable

---

1.2 16 words immediate recall

0

0

Mean Difference (IV, Fixed, 95% CI)

Not estimable

---

1.3 Ross Information Processing Assessment immediate memory

1

20

Mean Difference (IV, Fixed, 95% CI)

0.30 [-4.17, 4.77]

---

1.4 Wechsler Adult Intelligence Scales logical memory immediate recall

0

0

Mean Difference (IV, Fixed, 95% CI)

Not estimable

---

1.5 Rey auditory verbal learning trial I-V

0

0

Mean Difference (IV, Fixed, 95% CI)

Not estimable

---

 2 Executive functions

1

20

Mean Difference (IV, Fixed, 95% CI)

-2.30 [-4.49, -0.11]

---

2.1 Trailmaking part B

0

0

Mean Difference (IV, Fixed, 95% CI)

Not estimable

---

2.2 Ross Information Processing Assessment problem solving and abstract reasoning

1

20

Mean Difference (IV, Fixed, 95% CI)

-2.30 [-4.49, -0.11]

---

2.3 Wechsler Memory Scales mental control

0

0

Mean Difference (IV, Fixed, 95% CI)

Not estimable

---

2.4 Word comparison (#error)

0

0

Mean Difference (IV, Fixed, 95% CI)

Not estimable

---

2.5 Task switching paradigm (accuracy)

0

0

Mean Difference (IV, Fixed, 95% CI)

Not estimable

---

2.6 Verbal fluency

0

0

Mean Difference (IV, Fixed, 95% CI)

Not estimable

---

 3 Perception

1

20

Mean Difference (IV, Fixed, 95% CI)

-0.5 [-2.93, 1.93]

---

3.1 Face recognition (delayed recall)

0

0

Mean Difference (IV, Fixed, 95% CI)

Not estimable

---

3.2 Ross Information Processing Assessment auditory processing

1

20

Mean Difference (IV, Fixed, 95% CI)

-0.5 [-2.93, 1.93]

---

3.3 Wechsler Adult Intelligence Scales visual reproduction

0

0

Mean Difference (IV, Fixed, 95% CI)

Not estimable

---

 

Table 1. CLEAR NPT checklist items

---

1	Was the generation of allocation sequences adequate?
2	Was the treatment allocation concealed?
3	Were the details of the intervention administered to each group made available?#
4	Were care providers' experience or skill* in each arm appropriate?**
5	Was participant (i.e., patients) adherence assessed quantitatively? ^
6	Were participants adequately blinded?
6.1.1	If participants were not adequately blinded, were all other treatments and care (cointerventions) the same in each randomised group?
6.1.2	If participants were not adequately blinded, were withdrawals and lost to follow-up the same in each randomised group?
7	Were care providers or persons caring for the participants adequately blinded?
7.1.1	If care providers were not adequately blinded, were all other treatments and care (cointerventions) the same in each randomised group?
7.1.2	If care providers were not adequately blinded, were withdrawals and losses to follow-up the same in each randomised group?
8	Were outcome assessors adequately blinded to assess the primary outcomes?
8.1.1	If outcome assessors were not adequately blinded, were specific methods used to avoid ascertainment bias?§
9	Was the follow-up schedule the same in each group? §§
10	Were the main outcomes analysed according to the intention-to-treat principle?
#	The answer should be "Yes" if these data are either described in the reoprt or made available for each arm (reference to preliminary report, online addendum, etc.).
*	Care provider experience or skill will be assessed only for therapist-dependent interventions (where the succes of the intervention is directly linked to the providers' technical skill. For other treatment this item is not relevant and should be answered "Unclear".
**	Appropriate experience or skill should be determined according to published data, preliminary studies, guidelines, run-in period, or a group of experts and should be specified in the protocol for each study arm before the beginning of the survey.
^	Treatment adherence will be assessed only for the treatments necessitating iterative interventions (physiotherapy that supposes several sessions, in contrast to a one-shot treatment such as surgery). For one-shot treatments, this item is not relevant and should be answered "Unclear".
§	The answer is "0" if the answer to 8 is "Yes". The answer should be "Yes" if the main outcome is objective or hard, or if outcomes were assessed by a blinded or at least an independent endpoint review committee, or if outcomes were assessed by an independent outcome assessor trained to perform the measurements in a standardised manner, or if the outcome assessor was blinded to the study purpose and hypothesis.
§§	This item is not relevant if follow-up is part of the question. For example, this item is not relevant for a trial assessing frequent versus less frequent follow-up for cancer recurrence. In these situations, this item should be answered "Unclear".
	For items 6, 7 and 8 a score of 1 was given for a "Yes", a score of 2 for "No, because blinding is not feasible", a score of 3 for "No, although blinding is feasible" and a score of 4 for "Unclear". The other items of the checklist (1-5, 6.1.1., 6.1.2., 7.1.1., 7.1.2., 8.1.1., 9 and 10) were given a score of 1 for "Yes", 2 for "No" and 3 for "Unclear".

---

 

Table 2. Grouping of cognitive tests and studies over cognitive functions

---

Cognitive speed	Simple RT	Panton 1990
	Choice RT	Hassmèn 1997, Whitehurst 1991
	Trailmaking part A	Emery 1998
	Digit symbol substitution	Blumenthal 1989, Kramer 2001, Emery 1990 a
Verbal memory functions (immediate)	Randt memory test story recall	Blumenthal 1989
	16 words immediate recall	Hassmèn 1997
	Ross Information Processing Assessment memory immediate recall	Moul 1995
	Wechsler Adult Intelligence Scales logical memory immediate recall	Fabre 2002
	Rey auditory verbal learning test trail I-V	Kramer 2001
Visual memory functions (immediate)	Benton visual retention	Blumenthal 1989
	Wechsler Memory Scales visual reproduction immediate recall	Fabre 2002
Working memory	Digit span backward	Blumenthal 1989, Kramer 2001
Memory function (delayed)	16 words delayed recall	Hassmèn 1997
	Rey auditory verbal learning test delayed recall trail	Kramer 2001
Executive functions	Trailmaking part B	Blumenthal 1989
	Ross Information Processing Assessment problem solving and abstract reasoning	Moul 1995
	Wechsler Memory Scales mental control	Fabre 2002
	Word comparison	Madden 1989
	Task switching paradigm	Kramer 2001
	Verbal fluency	Emery 1998
Perception	Face recognition	Hassmèn 1997, Kramer 2001
	Ross Information Processing Assessment auditory processing	Moul 1995
	Wechsler Adult Intelligence Scales visual reproduction	Fabre 2002
Cognitive inhibition	Stroop color word test	Blumenthal 1989
	Stopping task	Kramer 2001
Visual attention	Digit vigilance	Emery 1998
	Tracking	Bakken 2001
	2&7 test	Blumenthal 1989
	Letter search	Madden 1989
	Visual search	Kramer 2001
Auditory attention	Digit span forward	Blumenthal 1989, Emery 1990 a, Fabre 2002, Hassmèn 1997, Kramer 2001
Motor function	Finger tapping	Bakken 2001, Blumenthal 1989, Emery 1998
	Pursuit rotor task	Kramer 2001

---

 

Table 3. Methodological quality of included studies (CLEAR NPT score)

---

Study ID	1 / 2	3	4	5	6 / 6.1.1. / 6.1.2	7 / 7.1.1. / 7.1.2.	8 / 8.1.1	9	10
Bakken 2001	3 / 3	1	3	1	2 / 3 / 2	2 / 3 / 2	4 / 1	1	2
Blumenthal 1989	3 / 3	1	3	1	2 / 2 / 2	2 / 2 / 2	4 / 3	1	3
Emery 1990 a	3 / 3	1	3	1	2 / 2 / 2	2 / 2 / 2	4 / 3	1	2
Emery 1998	1 / 1	1	3	1	2 / 2 / 2	2 / 2 / 2	1 / 0	1	2
Fabre 2002	3 / 3	1	3	2	2 / 1 / 1	2 / 1 / 1	4 / 3	1	1
Hassmén 1997	3 / 2	1	3	3	2 / 3 / 1	2 / 3 / 1	4 / 3	1	1
Kramer 2001	3 / 3	1	3	1	2 / 3 / 1	2 / 3 / 1	4 / 3	1	2
Madden 1989	3 / 3	1	3	1	2 / 3 / 2	2 / 3 / 2	4 / 3	1	2
Moul 1995	3 / 3	1	3	3	2 / 3 / 1	2 / 3 / 1	4 / 3	1	1
Panton 1990	3 / 3	1	3	2	2 / 3 / 3	2 / 3 / 3	4 / 3	1	2
Whitehurst 1991	3 / 3	1	3	2	2 / 3 / 3	2 / 3 / 3	4 / 3	1	3

---