Aerobic exercise effects upon cognition in Alzheimer's

Archives Italiennes de Biologie, 156: 54-63, 2018. DOI 10.12871/00039829201816

Aerobic exercise effects upon cognition in Alzheimer’s Disease: A systematic review of randomized controlled trials D.M. CAMMISULI1, A. INNOCENTI1,2, J. FUSI3, F. FRANZONI3, C. PRUNETI1,2 Department of Medicine and Surgery, Laboratory of Clinical Psychology, Psychophysiology and Clinical Neuropsychology, University of Parma, via Volturno 39, 43126 Parma, Italy; 2 Centre of Sport Medicine and Physical Exercise Centre (SEM), University of Parma, via Gramsci 40, 43126 Parma, Italy; 3 Department of Clinical and Experimental Medicine, Sport Medicine Unit, University of Pisa, via Savi 10, 56126 Pisa, Italy. 1

ABSTRACT Background. Previous reviews and meta-analysis have shown that physical activity has positive effects on cognition in healthy elderly as well as in patients with Mild Cognitive Impairment, even if with a minor effect whereas less is known about the effectiveness of aerobic exercise in patients with Alzheimer’s Disease (AD). Objectives. The aim of the present study was to systematically review the evidence from randomized controlled trials (RCTs) designed to evaluate aerobic exercise effects upon cognition in AD patients. Methods. PubMed, Cochrane, Web of Science and DARE databases were analytically searched for RCTs including aerobic exercise interventions for AD patients. Results. There is scarce evidence that aerobic exercise improves cognition in AD patients. Overall, the included studies reported only positive effects for patients’ global cognition after intervention, mainly due to a lack of accurate neuropsychological assessment of each cognitive domain. Whether the benefits of exercise are evident in all stages of AD pathology remain also uncertain. Conclusions. Standardized protocols, larger and more rigorous RCTs with long-term follow-ups may provide better insight into the effects of aerobic exercise on cognitive deterioration characterizing people with AD. Key words Alzheimer’s disease • Aerobic exercise • Cognition • Non-pharmacological intervention • Randomized controlled trial

Introduction According to the estimation of Word Health Organization (2012), 47.5 million people are living with dementia and 7.7 million new diagnoses are given every year worldwide. Alzheimer’s Disease (AD) currently is the most relevant neurodegenerative disease representing 50-75% of all dementia cases and the fifth leading cause of death among older adults, with no effective cure and preventing therapy (Gallaway et al., 2017). Severe

and progressive cognitive deterioration determines functional impairment of patients that is a core symptom of AD, with implications for personal and instrumental autonomy of daily living, depression and social restriction (Dalle Carbonare et al., 2009). Beyond advanced aging, Apolipoprotein E (APOE) ε4 (Huynh et al., 2017), amnestic Mild Cognitive Impairment multiple domain (Cammisuli et al., 2012; Petersen et al., 2009) and even depression (Diniz et al., 2013), cardiovascular disease represents another relevant risk factor for AD onset (Bondi et al., 2008).

Corresponding author: Dr. Davide Maria Cammisuli, Ph.D., Department of Medicine and Surgery, Laboratory of Clinical Psychology, Psychophysiology and Clinical Neuropsychology, University of Parma, via Volturno 39, 43126 Parma, Italy - Tel: +39 0521 034829 - Fax: +39 0521 034812 - Email: [email protected]

AEROBIC EXERCISE AND AD: A REVIEW

Non-pharmacological interventions are complementary strategies of pharmacological treatment (i.e., acetylcholinesterase inhibitors) helping in preserving functional and cognitive status of AD patients, reducing neuropsychiatric symptoms, improving quality of life and decreasing caregivers’ burden (Cammisuli et al., 2016). Among these interventions, there is an increasing interest in the pivotal role of aerobic exercise as a complementary strategy able to improve physical fitness and mental health of people with AD. Aerobic exercises include low-impact activities that people should do regularly to get fit, such as walking, jogging, swimming, aquarobics, cycling, etc. at a certain intensity over a relatively long time period (over 20 minutes). They cab be also adapted to elderly people specifically, to adequately match energy muscles demands via cardiovascular system. Cognitive functionality of AD patients may take advantage from regular aerobic exercise, particularly for executive functions sustaining patients’ autonomy of daily living (Farina et al., 2014). Aerobic exercise reduces blood pressure, arterial stiffness, oxidative stress, systemic inflammation and enhances endothelial function, too (Forbes et al., 2008). There are few studies investigating the effects of physical exercise on the cognitive performance of demented people. In a meta-analysis (Eggermont et al., 2006), eight studies were included reporting overall positive effects upon cognition, mainly in global cognitive function, executive functions, attention, memory and communication but only five had enough data to obtain an effect size ranging from small to moderate (Cohen’s d: 0.20-0.50) and only four having controls. A systematic review (Coelho et al., 2009) concluded that practicing a regular systematized physical activity contributes to the preservation of cognitive functions in AD but it was unable to establish a protocol of recommendation about its type and intensity. More recently, Groot et al. (2016) found an overall positive effect of physical activity in patients with dementia specifically driven by aerobic exercise. Brain alterations in AD preclinical phase patients occur before the onset of overt AD (De Carli et al., 2007; Pike et al., 2007). In humans, brain imaging studies suggested that high levels of cardiorespiratory fitness and aerobic exercise in heathy elderly is associated with reduced age-related atrophy and

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increased perfusion in brain areas sustaining executive functions and memory that represent the most vulnerable cognitive domains to the aging effects (Baker et al., 2010). Moreover, increased cardiorespiratory fitness attenuates the influence of amyloid on cognition (Schultz et al., 2015). Thus, a physical active lifestyle may ameliorate AD-related pathology and improve cognitive functioning. Cross-sectional studies in AD demonstrated that cardiorespiratory fitness is positively correlated to the whole brain and medial temporal volume, slower progression of clinical symptoms and brain atrophy (Hoffmann et al., 2016). In early stages of AD pathology, the cognitive impairment is mainly characterized by memory defect, given that marked atrophy is detected in the medial temporal and posterior cingulate/retrosplenial cortex and less in orbitofrontal cortex; later, pathology progression from incipient to mild AD involved lateral temporal cortex, dorsal parietal and frontal cortex together with the occurrence of cognitive deficits in extra-memory domains, such as language, visuo-constructive abilities and especially on executive functions. Finally, at ultimate stages new affected areas are the sensorimotor and visual cortices (Pini et al., 2016). Previous meta-analyses of RCTs showed that physical exercise in healthy adults is associated to cognitive improvement, larger hippocampal volumes, attenuation of age-related grey matter volume loss, and improved connectivity of brain networks (Ahlskog et al., 2011). MCI is a transitional state between physiological aging and dementia. It overlaps with both cognitive state associated to aging process and the onset of AD, so that it represents a critical time frame to promote physical health with positive implications for maintaining cognitive functioning. Beyond elderly people, current evidence supports the effectiveness of aerobic exercise also for mild cognitive decliners (Cammisuli et al., 2017), so that it may constitute a promising area of research also for people with overt dementia, in order to counteract a more severe cognitive deterioration and preserve at highest level personal and instrumental autonomy in daily life activities. The aim of this study was to systematically examine the evidence from randomized controlled trials (RCTs) on the effects of aerobic exercise upon cognition in AD, by overcoming previous reviews

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D.M. CAMMISULI ET AL.

incorporating other physical interventions than aerobic exercise or neglecting in differentiating between subtypes of dementia (Coelho et al., 2009; Groot et al., 2016; Penrose et al., 2005; Littbrand et al., 2011; Heyn et al., 2004; Öhman et al., 2014; Farina et al., 2014).

Methods PubMed, Cochrane Library, Web of Science and DARE (Database of Abstract of Reviews of Effects) databases were systematically examined for RCTs using the following terms: “Alzheimer’s Disease” AND “aerobic exercise” AND “cognition”. The search was performed on March 2017 and repeated on May 2017. Additional titles were added based on bibliographies of relevant issues and through the use of hand searches of journals and other pertinent resources. The studies from the literature search were selected from initial search if the met the following criteria: (1) patients with probable AD; (2) aerobic exercise as main intervention (multicomponent interventions were potentially eligible for inclusion as long as they included aerobic exercise as principal practice); (3) randomized controlled trial as study design; (4) any validate standardized neuropsychological test of cognition reported at baseline and followup. Exclusion criteria encompassed: (1) studies recruiting individuals with neurological diseases different from AD (i.e., other dementia types or vascular dementia, MCI, stroke, multiple sclerosis, traumatic brain injury, Parkinson’s Disease, focal brain disorders, etc.), psychiatric diseases and other comorbid medical conditions; (2) aerobic exercise in sport practices; (3) manuscripts written in other languages than English. This screening finally yielded 8 studies to be evaluated (Figure 1) (Moher et al., 2010; Liberati et al., 2009). Three independent reviewers (D.M.C., A.I., and C.P.) assessed the included studies for their methodological quality (Table 1). Disagreement was discussed until a consensus was definitively reached. A specific rating system to estimate methodological quality was used: the selected manuscripts were first checked by modified criteria for RCTs examining the effects of exercise intervention on cognition (Öhman et al., 2014) and the assessment of risk of bias was evaluated by the first author (D.M.C.) and confirmed by independent researchers (J.F., F.F.)

Tab. 1. - Evaluation of the quality criteria fulfilment in RCTs examining the effects of exercise intervention on cognition. Study

1

2

3

4

5

Kemoun et al., 2010

+

+/–

–

+

+/–

Venturelli et al., 2011

–

–

–

+

+/–

Vreugdenhil et al., 2012

+

+

–

+

–

Arcoverde et al., 2013

+

+

–

+

+

Yang et al., 2015

–

+

+

+

–

Hoffmann et al., 2016

+

+

+

+

+

Öhman et al., 2016

+

+

+

+

+

Morris et al., 2017

–

+

+

+

+

Note: (1) The diagnosis of Alzheimer’s Disease is based on validated criteria (NINCDS-ADRDA, 1984; APA, 2000; 2013); (2) Inclusion and exclusion criteria of the study are specifically described; (3) The study has sufficient statistical power (n ≥ 25 per group); (4) Intervention, measurements and outcome measurements are correctly described; (5) Complications and patients’ adherence are taken into accou

using the Quality Assessment Tool for Quantitative Studies (Thomas et al., 2004) (Table 2).

Results Overall, the quality of the included trials was moderate. Results from 8 studies (Kemoun et al., 2010; Venturelli et al., 2011; Vreugdenhil et al. 2012; Arcoverde et al., 2014; Hoffmann et al., 2016; Yang et al., 2015; Öhman et al., 2016; Morris et al., 2017) selected from 557 ones originally found are summarized in Table 3. If our previous investigation has suggested that aerobic exercise has positive effects on global cognition or executive functioning in individuals with MCI (Cammisuli et al., 2017), the present study showed that such an association was not so clear for people with AD. Six studies of the eight included used Mini Mental State Examination (MMSE) (Folstein et al., 1975) to assess the effect of aerobic exercise on global cognition of which three studies in addition to Alzheimer’s disease Assessment Scale-Cognitive Subscale (ADAS-cog) (Rosen et al., 1984). The MMSE is widely used in clinical practice but it is less informative than other tests, such as Montreal Cognitive Assessment (MoCA) (Julayanont et al., 2012), so that it has a limited power due to poorer psychometric properties. Nevertheless, these studies reported benefits for global cognition of AD patients after intervention, as revealed by an improved performance on the MMSE.

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Fig. 1. - Flow diagrams: study selection criteria.

Tab. 2. - Quality assessment of the included RCT studies. Study

Selection bias

Study design

Confounders

Blinding

Data collection

Withdrawal

Overall

Kemoun et al., 2010

*

***

***

**

***

***

**


**

***

***

**

***

***

***


**

***

***

**

***

***

***


**

***

*

**

***

***

**

Yang et al., 2015

*

**

*

*

***

*

*


***

***

***

***

***

***

***

Öhman et al., 2016

***

***

*

*

***

***

**

Morris et al., 2017

*

**

***

**

***

***

**

Note: * = Weak quality; ** = Moderate quality; *** = High quality

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Tab. 3. - Summary of main results of the selected studies. Study

Participants

Groups

Kemoun et al., 2010

31 elderly nursing home residents patients with probable AD Sex: Not specified; Age (mean): 81.8

Intervention group: physical activity program; Controls: no intervention


21 elderly nursing home residents with probable AD Sex: M=0; F=24 Age (mean): 84.5

Intervention group: physical activity program; Controls: routine care control group


Intervention group: 40 community- home dwelling support individuals Exercise with probable Program AD and their for the frail careers; elderly by Sex: M=16; Canadian F=24; Centre for Age (mean): Activity and 74.1 Aging; Controls: no intervention


16 patients with probable AD Sex: M= 8; F=8; Age (range): 62-82

Intervention group: physical activity program; Controls: no intervention

Yang et al., 2015

50 patients with AD Sex: Age (range): 50-80

Intervention group: physical activity program; Controls: Educational

Intervention

Aerobic exercise

3d/wk 60 minutes 15-week

Walking and ergocycle at 60-70% of maximum heart rate

4d/wk 30 minutes 6-month

Walking

d/wk 30 minutes 4-month

Brisk walking (plus strength and balance training)


Three phases: 1) warm-up exercise on the treadmill for 10 minutes at the intensity of 40% VO2max; 2) 20 minutes at the intensity of 60%% VO2max; 3) 5 minutes of supervised stretching.


70% maximum heart rate of cycling training

Cognitive assessment

ERFCFrench Version

MMSE

MMSE ADAS-Cog

MMSE CAMCOG RAVLT Digit Span

MMSE ADAS-Cog

Follow-ups

Main findings pertaining intervention groups

15-week

The intervention group had a slower decline in global cognition than control group

24-week

The intervention group had a slower decline in global cognition than the control group

16-week

Participation in a communitybased exercise program improves global cognition

16-week

The intervention group improved global cognition while control group declined.

12-week

MMSE score improvement and ADASCOG score decrease after the intervention (It follows)

59


Tab. 3. - Summary of main results of the selected studies. (It follows) Study


Öhman et al., 2016

Morris et al., 2017

Participants

Groups

200 patients with probable AD Sex: M=87; F=113 Age (mean): 70.5

Intervention group: Moderateto high intensity physical activity program; Controls: no intervention

Intervention

Aerobic exercise

Cognitive assessment


Patients performed aerobic exercise (3 x 10 minutes on a ergometer bicycle, cross trainer, and treadmill 2-5 minutes rest between)

MMSE SDMT ADAS-Cog SCWT VF

GE: rowing machine, Nordic walking outdoors, dancing; HE: exercise bike, pedal exerciser, Nordic walking outdoors. In addition to aerobic exercise, GE and HE performed strength and balance training as well as executive function training associated to aerobic exercise.

MMSE CDT VF

Not specified

Logical Memory FCSRT BNT Digit Span Category Fluency D-KEFS SCWT

120 communitydwelling dyads of individuals with probable AD and their spousal caregiver; Sex: M= 129; F=81 Age (range): 72-83

Intervention groups: A. homebased exercise (HE); B. groupbased exercise (GE); Controls: Usual community care

HE: 2d/wk 1-hour per session for 12 months GE: 2d/wk 4-hour session 12-month

76 older adults with probable AD Sex: M=37; F= 39; Age (mean): 72.9

Intervention group: physical activity program Controls: non-aerobic exercise (stretching and tonic exercise)

3-5 d/wk 60 minutes in week 1 until participants achieved 150 minutes per week (by adding approximately 21 minutes each week after week 1) 26-week

Follow-ups

Main findings pertaining intervention groups

16-week

No significant difference after the intervention on cognitive tests

12, 24, 48-week

Regular, long-term HE improved executive function (CDT, VF) of communitydwelling AD patients

13-, 26week

No clear effect of intervention on memory and executive functions

Note: ERFC= Rapid Evaluation of Cognitive Function; MMSE= Mini Mental State Examination; ADAS-COG: Alzheimer’s Disease Assessment Scale; CAMCOG= Cambridge Cognitive Examination; RAVLT= Rey Auditory Verbal Learning Test; SDMT= Symbol Digit Modalities Test; SCWT= Stroop Colour Word Interference Test; VF= Verbal Fluency; CDT= Clock Drawing Test; VF= verbal fluency; FCSRT= Free and Cued Selective Reminding Test; BNT= Boston Naming Test; D-KEFS = Delis-Kaplan Executive Function System.

60


AD begins with an episodic memory deterioration linked to the involvement of hippocampal formation, temporal disorientation and occasional anomies followed by the progressive and sequential failure of attentive and executive functions, language deficits, visual agnosia and constructive apraxia (Bondi et al., 2008). Only some specific frontal domains were tested by the researchers, including inhibitory control and generation of appropriate novel response (i.e., verbal or category fluency) without assessing cognitive flexibility and set shifting which reduction often takes place in AD (Bondi et al., 2008). Furthermore, attention/working memory deficit and declarative memory testing was underestimated. Finally, only one study screened for altered visuoconstructive abilities typically characterizing AD in later stages. Research would benefit from assessing molecular markers/neuroimaging to determine optimal intervention characteristics of aerobic training. Just barely two studies used these indicators. Yang et al. (2015) showed that APO-a1 increased significantly in the intervention group after a 3-month aerobic exercise: decreased APO-a1 levels were associated with the severity of AD and lipid metabolism during remyelination and axonal regeneration. Morris et al. (2017) found indirect evidence that exercise-related gains in cardiorespiratory fitness were associated to reduced hippocampal atrophy constituting a hallmark of AD. Methodological limitations of the selected studies included blinding, samples size, incomplete results and selective reporting, variations in outcomes measure and unsupervised intervention programs. Moreover, whether the benefits of exercise are evident in all stages of dementia remains uncertain, so that measuring the effectiveness of exercise on cognition is a challenge of future research also because of the progressive nature of AD and its negative implications for people’s health on social, emotional and cognitive functioning at different stages. Aerobic exercise programs for people in the advanced stages of AD are complicated by many factors, such as anxiety, depression, sadness, anger, denial, motor complications and behavioural disturbances that should be considered when interventions are designed. As things stand, it is not possible to estimate if aerobic exercise gains are maintained after the intervention. Thus, longitudinal studies are welcome, too.

Summary On the basis of the present findings, AD patients may benefit from aerobic exercise intervention for improving global cognition, especially in the mildmoderate phase of the disease. We cannot conclude that it definitely promotes a positive effect upon cognition, due to the lack of an in-depth neurocognitive assessment through wide neuropsychological batteries, especially for visuospatial and constructive skills, language, spatial and temporal orientation domains that were never taken into account by the included studies. As well as for MCI patients, beyond a brain neuroprotective effects, regular aerobic exercise may attenuate cognitive deterioration in AD via mitigation of cerebrovascular risk factors and should be considered a strategy for preventing a more severe cognitive impairment (Cammisuli et al., 2017). Aerobic exercise is a low-cost, low-risk and widely available strategy to counteract AD consequences on the brain. According to Sallis et al. (2013), dementia rates could be reduced if people are physically active. As a consequence, this allow to preliminary advice mild AD patients, particularly those who are sedentary, to initiate daily aerobic exercise (Innocenti et al., 2017). Moreover, aerobic exercise may improve equilibrium capacity of AD patients and reduce risk of falls (Kemoun et al., 2010). According to Arcoverde et al. (2014), regular aerobic exercise gradually increased to achieve 60% of maximum heart rate or peak oxygen consumption per unit time (Vo2) and performed at least 30 minutes twice a week (of which 10 minutes of warm-up exercise at a minor intensity) seems to be reasonable for a good regimen. These parameters are comparable to the Recommendations reported by the American Heart Association and the American College of Sports Medicine suggesting that older people should do moderate-intensity aerobic exercise at least 30 minutes a day (Nelson et al., 2007). Aerobic exercise plan for people with AD should be simple, practical and realistic and involve caregiver. It should be made at different intensity in relation to the severity of AD stage. Therapists have to pay attention on special needs of AD patients, with regard to general medical condition, personal motivation and even depression when occurred. Improving aerobic capacity may also be essential in prevention of secondary diseases of AD patients reducing polypathology.


Additional research is need to address specific health care needs of AD patients, cost-effectiveness of aerobic training and interaction with pharmacological treatment, vitamin supplementation and cognitive rehabilitation (e.g., cognitive stimulation therapy). Supplementary investigation is necessary to explore the complex relationship between aerobic exercise and brain aging, including other influencing variables, such as diet and genetics to better understand all the mechanisms responsible for exercise protective effects against progressive cognitive deterioration. Standardized protocols, larger and more rigorous RCTs with long-term follow-ups including people at different stages (early to mild/moderate) of the disease (given appropriate medical conditions) may provide better insight into the critical role of aerobic exercise on mental health in people with AD. Determine specific effects of aerobic exercise intervention on cognitive outcome may inform management and sanitary strategies more accurately.

Acknowledgement We gratefully thank Salvatore Massimiliano Cammisuli for suggestive ideas.

Funding This study received no funding.

Conflict of interest None to declare.

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