Aerobic exercise improves quality of life, psychological well-being and systemic inflammation in subjects with Alzheimer’s disease.

Background: Alzheimer’s disease has a destructive drawbacks on the patient and his/her entire family as this disease badly affects the behavior, cognition and abilities to do activities of daily living (ADL). The physical and mental benefits of exercise are widely known but seldom available to persons suffering from Alzheimer’s disease. Objective: The aim of this study was to measure quality of life, systemic inflammation and psychological well-being response to aerobic exercises in Alzheimer’s. Methods: Forty Alzheimer elderly subjects were enrolled in two groups; the first group received treadmill aerobic exercise, while the second group was considered as a control group and received no training intervention for two months. Assessment of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), Rosenberg Self-Esteem Scale (RSES),Beck Depression Inventory (BDI), Profile of Mood States(POMS) and SF-36 health quality of life (SF-36 HRQL) were taken before and at the end of the study. Results: There was a 25.2%, 19.4%, 23.5%, 21.3%, 17.7% , 11.7%, 12.5% and 10.1 % reduction in mean values of TNF-α, IL-6, BDI, POMS, health transition SF-36 subscale, bodily pain SF-36 subscale, role functioning: emotional SF-36 subscale and mental health SF-36 subscale respectively in addition to 15.7%, 13.1%, 12.6%, 11.1%, 13.2% and 11.2 % increase in mean values of RSES, physical functioning SF-36 subscale, role functioning:physical SF-36 subscale, general health SF-36 subscale, Vitality SF-36 subscale and Social functioning SF-36 subscale respectively in group (A) received aerobic exercise training, so that there was a significant reduction in the mean values of TNF-α, IL-6, BDI & POMS and increase in the mean values of SF-36 HRQL subscale scores, RSES in group (A) as a result of aerobic exercise training, while the results of group (B) who received no train ing intervention were not significant. Also, there were significant differences between mean levels of the investigated parameters in group (A) and group (B) at the end of the study (P<0.05). Conclusion: Treadmill walking exercise training is an effective treatment policy to improve quality of life, systemic inflammation and psychological wellbeing in Alzheimer’s.


Introduction
Alzheimer's disease is a slowly progressive neuropsychiatric disorder affecting mainly the brain regions of cognition and memory 1 .Globally, Alzheimer's disease affects about 27 million people of elderly population, however this number is expected to triple by 2050 2 .Although, aging is the major risk factor in Alzheimer's disease, genetics can be considered have a risk of Alzheimer's disease 3 .The cost of Alzheimer's disease management is high as it is about $183 billion in United State of America, and is expected to be raised by 600% over the next 40 years 4 .Alzheimer's disease not only have a destructive drawbacks on the patient but on his entire family members as this disease badly affects the behavior, cognition and ability to do activities of daily living (ADL) 5 .
Several inflammatory mediators, including tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) are increased in Alzheimer's patients 6 .Several studies have established further the presence of inflammatory markers in the Alzheimer's disease brain 7 .CNS inflammation, impaired neuronal insulin signaling, and neuronal dysfunction in Alzheimer's disease may be a consequence of systemic inflammatory processes 8,9 .Neuro-inflammation plays an important role in Alzheimer's disease as well as in depression.Alzheimer's disease is often accompanied by symptoms of depression, anxiety, irritability, and mood instability 10,11 .Ultimately, this could contribute to or accelerate the onset of clinical manifestations of Alzheimer's disease 12 .
Psychiatric disturbances affect as many as 90% of patients with Alzheimer's disease and are a major focus of treatment.Depression is one of the most frequent psychiatric complications of Alzheimer's disease, affecting as many as 50% of patients [13][14][15] .
Aerobic exercise training is an effective and cost-efficient alternative therapy for disorders of anxiety and mood disorders 16 .Also, exercise training slows down the progression of cognitive decline 17 , improves performance on tests of cognition and psychological well-being 18 and enhances sleep quality 19 .However, the available previous studies involving the impact of exercise training upon the quality of life, psychological wellbeing along with systemic inflammation in Alzheimer's disease is limited in number 20 .
Aerobic exercise training is hypothesized to improve cognition, physical performance, functional ability and quality of life.However, the available previous studies involving the impact of exercise training upon the quality of life, psychological well-being along with systemic inflammation in Alzheimer's disease are limited in number; so this study aimed to measure quality of life, systemic inflammation and psychological well-being response to aerobic exercises in Alzheimer's.

Subjects
Forty elderly patients with Alzheimer's disease with age ranging from 65 to 75 years participated in this study.Exclusion criteria included smokers, subjects with pulmonary, cardiac, renal, hepatic, metabolic and neurological diseases.All the patients who participated in the study were non-smokers and continued on their ordinary diet throughout the study.Following pre-training testing, a randomized block procedure was used to assign qualified participants into two equal groups; group (A) received treadmill aerobic exercise, while the second group (B) was considered as a control group and received no training intervention for two months.The CONSORT diagram outlining the details of the screening, run-in and randomization phases of the study and reasons for participant exclusion figure (1).Informed consent was obtained from all participants.This study was approved by the Scientific Research Ethical Committee, Faculty of Applied Medical Sciences at King University.

Psychological well-being:
Assessment of psychological well-being included measurement of self-esteem and depression 21 .Self-esteem was evaluated using the Rosenberg Self-Esteem Scale (RSES) 22 , which included ten items to be answered on a four point Likert scale.Mood disturbance was measured by Profile of Mood States (POMS) 23 ; it assessed the transient emotional state by 65 items on a 5-point Likert scale.This questionnaire evaluated 6 dimensions of mood in order to detect a Total Mood Disturbance score.However, depression was measured using the Beck Depression Inventory (BDI), a twenty-one item was covered to detect the total score for measuring the symptoms of depression 24 .

Health-related quality of life (SF-36 HRQL):
Health-related quality of life was assessed by SF-36 which includes eight subscales: vitality, bodily pain, general health, physical functioning, social functioning, physical Role Functioning, emotional role functioning, and mental health.The SF-36 was a questionnaire for detecting the amount of change in their general health over the past year 25 .

Procedures
Following the previous evaluation, all participants were divided to the following groups: 1. Group (A) participated in treadmill aerobic exercise (Enraf Nonium, Model display panel Standard, NR 1475.801,Holand) which was conducted according to recommendation of aerobic exercise application for elderly approved by the American College of Sports Medicine and the National Institute on Aging [26][27] .Training program included 5 minutes for warming-up in the form of range motion and stretching exercises, 10-30 minutes of aerobic exercise training (60-70% of maximum heart rate) and 10 minutes of cooling down ( on treadmill with low speed and without inclination).Participants had 3 sessions/week for 2 months with close supervision by physical therapist.

Statistical analysis
The mean values of the investigated parameters obtained before and after two months in both groups were compared using paired "t" test.Independent "t" test was used for the comparison between the two groups (P<0.05).

Results
Table (1) shows the baseline characteristics of the participants who entered the trial.However, there was a 25.2%, 19  3).Also, there were significant differences between mean levels of the investigated parameters in group (A) and group (B) at the end of the study (table 4) (P<0.05).

Discussion
Despite the growing evidence on the benefits of exercise on the health and functioning of older adults with cognitive disorders, the available literature lacks clinical evidence that supports recommendations for exercise guidelines in people with Alzheimer's disease 28 .So, the aim of this study was to detect changes inquality of life, systemic inflammation and psychological wellbeing in response to aerobic exercise training inAlzheimer's.The results of the present study indicated that there was a significant reduction in mean values of Beck Depression Inventory (BDI) and Profile of Mood States(POMS) in response to aerobic exercise training in Alzheimer's.There is a growing body of evidence indicates that aerobic exercise is an effective and cost-efficient treatment alternative for a variety of anxiety and mood disorders, including panic disorder 29 .Craft found that a depressed group who undertook aerobic exercise for nine weeks had significantly higher coping efficacy than a non-exercise control 30 .In a sample of 101 healthy older adults randomized to four months of aerobic exercise, a yoga/flexibility control group, or wait list, assessment of scores from pre-to post-treatment revealed that depressive symptoms were reduced, especially in men 31 .Also, Blumenthal in his study on 156 community dwellers diagnosed with major depression who were randomized to supervised exercise, medication, or a combination of exercise and medication.The 16-week exercise treatment consisted of three weekly sessions of aerobic activity.By the end of the treatment period, each of the three treatment groups experienced a significant reduction in their levels of depression.The treatments did not differ significantly from one another in efficacy.These results suggest that exercise may be a viable alternative to medication in the treatment of depression in older adults 32  intensity exercise may be a helpful and effective adjuvant therapy for treatment-resistant major depression 33 .
A number of potential mechanisms may be responsible for the reductions in depression associated with physical exercise e.g.physiological mechanisms hypothesized include the central monoamine theory (i.e., exercise corrects dysregulation of the central monoamines believed to lead to depression), as well as consideration of the role of the hypothalamic-pituitary-adrenal (HPA) axis (i.e., some depressed individuals exhibit HPA hyperactivity in response to stress and exercise may regulate this activity) 34,35 .
Our results revealed that serum IL-6 and TNF-α were significantly decreased in response to aerobic exercise training in Alzheimer's.Our findings were consistent with Goldhammer et al. who found large (48%; 7.5 to 3.9 mg/L) reductions in serum CRP in 28 elderly coronary heart disease patients in response to 12 weeks of aerobic exercise training as offered in typical Phase II cardiac rehabilitation programs 36 .In a study by Kohut et al. sedentary, low fit older adults aged >64 years were randomized to moderate aerobic exercise training (65-80% heart rate reserve, 3 times per week, 30-45min/day) or flexibility control group for 10 months.Exercisers had a significant reduction in serum C reactive protein (CRP), IL-6, interleukin-18 (IL-18) and TNF-α when compared to the flexibility group 37 .Also, Nicklas et al. examined the effects of 12 months of moderate walking training on plasma CRP and IL-6.Four hundred and twenty four sedentary, overweight/obese (BMI >28), community-dwelling elderly (70-89 years) were randomized to treatment.The exercise intervention resulted in a significant 16% reduction in IL-6.CRP was 32% lower after exercise 38 .Moreover, Ogawa et al. found that 12 week of strength training significantly reduced serum CRP despite having no effect on body weight or waist circumference 39 .
The potential mechanisms of exercise training-induced reductions in inflammation in Alzheimer's disease patients include loss of adipose tissue which induced reductions in serum markers of inflammation 40,41 .Exercise training also increases vagal tone 42 , which according to the cholinergic anti-inflammatory reflex espoused by Tracy, could lead to reductions in systemic inflammation 43 .Acute exercise activates the hypothalamic-pituitary-adrenal axis and sympathetic nervous systems.Cortisol is known to have potent anti-inflammatory effects44 and catecholamine can inhibit pro-inflammatory cytokine production 45 .Several studies have demonstrated that exercise training can down regulate toll-like receptor 4, ligation of which activates pro-inflammatory cascades 46,47 .Furthermore, on analyzing the quality of life changes in response aerobic exercise training in Alzheimer's, we found a significant improvement in the mean values of SF-36 subscale scores.Our findings were consistent with several studies have shown that exercise intervention might enhance health-related quality of life and psychological well-being [48][49][50] .Mahendra conducted a randomized controlled trial for 3 months follow-up, percentage of participants exercising ≥ 60 min per week increased in the exercise group compared with routine care.Exercise improved levels of physical functioning (SF-36 score) and depression compared with people in routine care (whose levels worsened).At 24 months, longitudinal analyses of all follow-up data revealed improvements in exercise group physical functioning (SF-36) and mobility compared with routine care 51 .Also, Schmitz et al. conducted the German National Health Interview and Examination Survey (GHS) on 7,124 persons, 18-79 years of age.Results revealed that higher levels of physical activity were associated with higher health-related quality of life among persons with mental disorders and physically inactive subjects reported poorer quality of life 52 .Bowen et al. proved that 12-month exercise intervention (225 min/week) improved physical functioning and general health scores among sedentary postmenopausal women (vs.controls) 53 .Improved HRQOL was also noted in another 12-month exercise trial (60 min/day, 3 times/ week) among middle-aged adults 54 .While, Imayama et al. conducted a study one middle-aged women (n=100) and men(n=102) who were randomly assigned to either exercise (360 min/week of moderate-to-vigorous aerobic exercise) or control and HRQOL (SF-36)were assessed at baseline and 12 months and proved that this level of exercise may increase HRQOL among overweight men 55 .Similarly, a survey of European adults found that being physically active (≥ 24 MET-h/week) is associated with better mental health compared with being less active (≤24 MET-h/week) 56,57 .Moreover, Hoffmann etal.conducted a study of exercise sessions in a group of 3-5 participants for 1 hour, 3 times per week for 16 weeks.The purpose African Health Sciences Vol 16 Issue 4, December, 2016 of the first 4 weeks of exercise is to accustom the participants to exercising (adaptation exercise).During the next 12 weeks, the exercise is designed to achieve an intensity of 70-80% of heart rate reserve.Results proved that moderate intensity aerobic could improve cognition, quality of life, physical health and functional ability in patients with Alzheimer's disease 58 .
Although the exact mechanism for the effect of exercises on mental health is still unknown, several physiological and psychological mechanisms have been proposed, including increased feelings of self-efficacy, self-perceptions of control, reduced emotional strain and physiological responses to stress, and beneficial effects on neurotransmitters 59 .Also, physical activity may have a trophic effect on the brain, particularly the hippo-campus.For instance, exercise increases brain-derived neurotrophic factor (BDNF) 60 .Exercise appears to stimulate neurogenesis 61 , enhance neuronal survival 62 , increase resistance to brain insults 63,64 and increase synaptic plasticity 65 .Exercise promotes brain vascularization 66,67 , mobilizes gene expression profiles predicted to benefit brain plasticity 68 .Social contact may be an important mechanism, and subjects who take regular exercise may, as a result, get positive feedback from other people and an increased sense of self-worth 69 .
The current study has important strengths and limitations.The major strength is the supervised nature of the study.Supervising physical activity removes the need to question compliance or to rely on activity questionnaires.Furthermore, all exercise sessions were supervised and adherence to the activities was essentially 100%.Moreover, the study was randomized; hence, we can extrapolate adherence to the general population.On the other hand, the major limitations is only Alzheimer's patients were enrolled in the study, so the value of this study is only related to Alzheimer's in this age group, also the small sample size in both groups may limit the possibility of generalization of the findings in the present study , in addition, a number of confounders such as socioeconomic indicators like education level, previous occupation and income which should be controlled as they can affect the outcomes were not measured.Finally, within the limit of this study, aerobic exercise training is recommended for modulation of low grade systemic inflammation and poor quality of life among Alzheimer's.Further researches are needed to explore the impact of different therapeutic interventions on quality of life and other biochemical parameters among Alzheimer's.

Conclusion
The current study provides evidence that treadmill walking exercise training is an effective treatment policy to improve quality of life, systemic inflammation and psychological wellbeing in Alzheimer's.

Table ( 4): Mean value and significance of TNF-α, IL-6, RSES, BDI, POMS and SF-36 subscale scores in group (A) and group (B) at the end of the study.
BeckDepression Inventory; POM S: Profile of M ood States, (*) indicates a significant difference between the two groups, P < 0.05.