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NeuroRehabilitation 34 (2014) 209–213 DOI:10.3233/NRE-131020 IOS Press

Aerobic exercises enhance cognitive functions and brain derived neurotrophic factor in ischemic stroke patients

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Mohamed S. El-Tamawya , Foad Abd-Allaha,∗ , Sandra M. Ahmeda , Moshera H. Darwishb and Heba A. Khalifab a Department

of Neurology, Faculty of Medicine, Cairo University, Cairo, Egypt of Physical Therapy for Neuromuscular Disorders and its Surgery, Faculty for Physical Therapy, Cairo University, Cairo, Egypt

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Abstract. BACKGROUND: Stroke is a leading cause of functional impairments. High percentage of these patients will experience some degree of cognitive affection, ranging from mild cognitive impairment to dementia. OBJECTIVE: Demonstrate the role of aerobic exercises enhancing cognitive functions and its effect on Brain Derived Neurotrophic factor (BDNF) in post-ischemic stroke patients in the territory of anterior circulation. SUBJECTS AND METHODS: We included thirty Egyptian ischemic stroke patients in the territory of anterior circulation. They were divided into 2 groups; group 1 (G1) were subjected to physiotherapy program without aerobic exercises and group 2 (G2) were subjected to the same previous program followed by aerobic exercises. Both groups were subjected to pre- and post-treatment Addenbrookes’s Cognitive Examination- Revised (ACER) and serum level of BDNF. RESULTS: Our results showed a significant improvement in ACER score in G2 compared to G1 post-treatment (p = 0.017). BDNF serum level significantly increased in G2 post-treatment compared to pre-treatment (p = 0.001) and compared to G1 group (p = 0.0458). ACER improvement was positively correlated to increase in serum level of BDNF (r = 0.53, p = 0.044). CONCLUSION: Aerobic exercises improve cognitive functions of ischemic stroke patients. This improvement is related to the increase in serum level of BDNF. Keywords: Stroke, aerobic exercises, BDNF

1. Introduction Stroke is a leading cause of functional impairments; with 20% of survivors requiring institutional care after 3 months and 15% to 30% being permanently disabled (Goldstein et al., 2011). Although only few patients ∗ Address for correspondence: Foad Abd-Allah, MD. Address: Neurovascular Unit, Department of Neurology, Cairo University, Al-Manial, Cairo 11562, Egypt. Tel.: +20 1110110898; E-mail: [email protected].

become overtly demented after stroke, high percentage of mild cognitive impairment was found mostly in the field of mental speed and calculation. Most patients improve but some of them experience no improvement or might even deteriorate (MacLellan et al., 2011). Novel interventions to improve post-stroke impairment have been developed to make use of advances in neuroscience. This new field attempts to translate basic science research into clinical practice (Wu, Lin, Wolf, & Roby-Brami, 2012). Brain Derived Neurotrophic

1053-8135/14/$27.50 © 2014 – IOS Press and the authors. All rights reserved

M.S. El-Tamawy et al. / Aerobic exercises and cognitive functions in ischemic stroke

2. Subjects and methods

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physiotherapy program for “25–30” min. followed by a rest period for about “10–15” min, then aerobic exercise was done on a Bicycle ergometer (Monark Rehab trainer model 88 E) for “40–45”min as follow the first five to ten minutes of each session were dedicated to warming up exercise on the bicycle in the form of slow progression exercise (to decrease the risk of hypotension, musculoskeletal injury and cardiovascular complications), followed by the active phase of exercise for 30 min., and finally cooling down phase for five min. with intensity and speed decreased gradually until reaching the resting heart rate (RHR). The exercise program repeated three times per week for eight weeks. A single qualified physiotherapist performed the primary tests, continuous physiotherapy program and follow up assessment. The program was performed at the outpatient clinic of Neuro-Muscular Department, Faculty of Physical Therapy, Cairo University. After eight weeks patients in both groups were subjected to reassessment of cognitive functions using ACER. Both tests (before and after treatment) were performed by a neurologist trained to perform the ACER. The assessment was performed in a comfortable setting under optimal conditions. Levels of BDNF were assessed before and after the eight weeks of physiotherapy. Five milliliters of venous blood sample was collected on anticoagulant free tube (EDTA K3) in the morning before patients receive their treatment session. Samples were kept at room temperature for one hour followed by another hour at 4◦ C before sera were isolated. Sera were then stored at −70◦ C for batch assessment. Serum BDNF was measured by a solid-phase sandwich, two-site enzyme linked immunoassay (ELISA) using the BDNF Emax Immunassay System reagents. This was performed at Biochemistry Department laboratory, Cairo University. Our reference range was 18.9 ± 5.7 ng/ml (Rosenfeld et al., 1995).

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Factor (BDNF) is a member of the neurotrophins that play a role in increasing the brain’s resistance to damage and degeneration with aging and enhances long term memory and learning (Blaha, Raghupathi, Saatman, & McIntosh, 2000). Elderly women with higher mean of serum BDNF demonstrated significantly better scores in the tests of cognitive functions (Komulainen et al., 2008). Aerobic exercises were proved to initiate a series of biochemical reactions in the body and the brain of animals and humans (Edelberg & Reed, 2003; Molteni, Ying, & Gómez-Pinilla, 2002; Sutoo & Akiyama, 2003). One of these changes involve increase of the BDNF following running in rodents (Johnson, Rhodes, Jeffrey, Garland, & Mitchell, 2003). In humans high exercise intensity was needed to increase BDNF (Ferris, Williams, & Shen, 2007). Our goal is to demonstrate the enhancing effect of aerobic exercises on cognitive functions and serum level of BDNF in post-ischemic stroke patients in the territory of anterior circulation.

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We studied 30 Egyptian stroke patients proved to have some degree of cognitive impairment following strokes in the territory of anterior circulation. Cognitive assessment was done using the Addenbrooke’s Cognitive Examination- Revised (ACER) (Mioshi, Dawson, Mitchell, Arnold, & Hodges, 2006). Patients with a score less than 82 were included. All patients were educated. There were male predominance in our sample (n = 21/30) but males/females ratio was close to each other in both groups (G1 10/5, G2 11/4). Mean age was 48.4 ± 6.39 years. Duration of illness ranged from 3–18 months. All patients were medically and psychologically stable and of adequate cardiac function. We excluded patients with multiple strokes, previous cognitive, mental, visual, auditory, neurological problems and also cardiac diseases. The study population was divided into two equal groups of fifteen patients each; group 1 (G1) (considered as the control group) were treated by a designed physiotherapy program. This program was applied for “25–30” minute per session, three times per week, day after day for successive eight weeks. This program consisted of stretching exercises, facilitation for weak muscles, strengthening exercise, postural control and balance, functional training and gait training. Group 2 (G2) (study group) were treated by the same designed

3. Statistical analysis The obtained data were collected and statistically analyzed using the arithmetic mean and their standard deviation. Paired t-test was used for comparison of means of pre and post treatment within each group. Unpaired t-test for comparison of means of pre and post treatment of two independent groups. Pearson rank correlation test to correlate between variables post-treatment in study group (Kirkwood, Sterne, & Kirkwood, 2003).


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Fig. 1. Scatter plot showing positive correlation between the mean value of changes in total score of ACER test and level of serum BDNF in (G2).

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group. This means that improvement in cognitive function is consistent with improvement of serum BDNF level as shown in Fig. 1.

5. Discussion

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No statistically significant difference (p > 0.05) was found between both groups regarding baseline characteristics including age, gender, body mass index, pretreatment ACER score and serum level of BDNF as shown in Table 1. Comparison of ACER total scores post-treatment in (G1) and (G2) showed a statistically significant difference with increased values in the (G2) group; 75.93 ± 4.9 and 81.07 ± 6.16 respectively (p = 0.017). The mean values of the subtest domains (attention, memory, verbal fluency, language and visuospatial ability variables) post treatment in (G1) were 15.47 ± 1.96, 19.07 ± 2.6, 2 ± 1.25, 25.53 ± 1.13 and 13.87 ± 1.4 respectively, in (G2) were 16.87 ± 1.5, 21.27 ± 3.15, 2.6 ± 1.1, 25.27 ± 1.4 and 15.07 ± 1.28 respectively. Comparison of the mean value of each domain in (G1) with the corresponding mean value in (G2) revealed a significant increase in all domains in G2 (p < 0.05) except for verbal fluency and language domains (p = 0.18 and 0.58 respectively). Pre- and post-treatment serum level of BDNF did not show a significant difference in control group (G1) (p = 0.698) but in study group (G2) there was a high statistical difference (p = 0.0001) as shown in Table 2. Pearson rank correlation between the post treatment changes in total score of ACER test and level of serum BDNF in (G2) was statistically significant(r = 0.53, p = 0.044).The result indicated significant positive correlation between improvement in total score of ACER test and increase in serum BDNF level in the study

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4. Results

Table 1 Age, Body Mass Index (BMI), ACER score and BDNF serum level mean ± SD in both groups Variant

G1

Age (years) Body mass index (kg/m2 ) ACER score BDNF serum level ng/ml

49.67 ± 6.98 25.26 ± 1.84 74.47 ± 5.58 20.48 ± 3.4

G2

p value

48.4 ± 6.39 25.75 ± 2.16 73.47 ± 6.2 19.18 ± 3.71

0.60 0.51 0.65 0.32

Table 2 Comparison of BDNF serum level in both groups pre- and post-treatment BDNF serum level ng/ml Pre- treatment Post- treatment G1 G2 t value P value

20.48 ± 3.4 19.18 ± 3.71 1.004 0.324

20.66 ± 2.77 23.83 ± 5.18 2.09 0.0458*

*Statistically significant p < 0.05.

t value

p value

0.396 5.547

0.698 0.0001* – –

Findings of the present study show that aerobic exercises following an acute ischemic stroke in the territory of anterior circulation significantly improve cognitive functions measured in this study by ACER. This improvement is accompanied by an increase in the level of the serum level of BDNF. There was a significant difference between both groups (G1) and (G2) post-treatment; we found that aerobic exercises added to the physiotherapy program of (G2) was reflected on the ACER test as there was improvement in the total scores of this group. This improvement may be attributed to the physiological effect of aerobic exercise on brain as it increases the cerebral tissue oxygenation, blood flow velocity and cerebral metabolism and homeostasis which in turn improve the speed of information processing, motor learning, implicit memory and executive function (McAuley, Kramer, & Colcombe, 2004; Quaney et al., 2009; Rand, Eng, Liu-Ambrose, & Tawashy, 2010). The serum level of BDNF was measured as a biomarker of improvement. BDNF produces neurogenesis and synaptogenesis. It increases resistance to brain insult and improves learning and mental performance (Griffin et al., 2011) We choose the serum level of BDNF as it was proved that there was a strong correlation between serum and cortical BDNF levels as it undergoes bidirectional transport across the blood–brain barrier (Lee et al., 2008).


patients. This improvement is strongly correlated to the elevation in BDNF. Aerobic exercises should be added as an essential therapeutic modality to assist in the rehabilitation program of stroke patients.

Declaration of interest None.

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References

Alder, J., Kramer, B. C., Hoskin, C., & Thakker-Varia, S. (2012). Brain-derived neurotrophic factor produced by human umbilical tissue-derived cells is required for its effect on hippocampal dendritic differentiation. Dev Neurobiol, 72(6), 755-765. Blaha, G. R., Raghupathi, R., Saatman, K. E., & McIntosh, T. K. (2000). Brain-derived neurotrophic factor administration after traumatic brain injury in the rat does not protect against behavioral or histological deficits. Neuroscience, 99(3), 483-493. Ding, Y. H., Li, J., Zhou, Y., Rafols, J. A., Clark, J. C., & Ding, Y. (2006). Cerebral angiogenesis and expression of angiogenic factors in aging rats after exercise. Curr Neurovasc Res, 3(1), 15-23. Edelberg, J. M., & Reed, M. J. (2003). Aging and angiogenesis. Front Biosci, 8, s1199-s1209. Erickson, K. I., Voss, M. W., Prakash, R. S., Basak, C., Szabo, A., Chaddock, L., et al. (2011). Exercise training increases size of hippocampus and improves memory. Proc Natl Acad Sci U S A, 108(7), 3017-3022. Ferris, L. T., Williams, J. S., & Shen, C. L. (2007). The effect of acute exercise on serum brain-derived neurotrophic factor levels and cognitive function. Med Sci Sports Exerc, 39(4), 728-734. Goldstein, L. B., Bushnell, C. D., Adams, R. J., Appel, L. J., Braun, L. T., Chaturvedi, S., et al. (2011). Guidelines for the primary prevention of stroke: A guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke, 42(2), 517-584. ´ Mullally, S., Foley, C., Warmington, S. A., O’Mara, S. M., Griffin, E., & Kelly, A. M. (2011). Aerobic exercise improves hippocampal function and increases BDNF in the serum of young adult males. Physiol Behav, 104(5), 934-941. Johnson, R. A., Rhodes, J. S., Jeffrey, S. L., Garland, T., & Mitchell, G. S. (2003). Hippocampal brain-derived neurotrophic factor but not neurotrophin-3 increases more in mice selected for increased voluntary wheel running. Neuroscience, 121(1), 1-7. Kirkwood, B. R., Sterne, J. A. C., & Kirkwood, B. R. E. o. m. s. (2003). Essential medical statistics (2nd ed, / Betty R. Kirkwood. Jonathan A.C. Sterne. ed.). Malden, Mass.; Oxford Blackwell Science. Komulainen, P., Pedersen, M., Hänninen, T., Bruunsgaard, H., Lakka, T. A., Kivipelto, M., et al. (2008). BDNF is a novel marker of cognitive function in ageing women: The DR’s EXTRA Study. Neurobiol Learn Mem, 90(4), 596-603. Lee, T. H., Yang, J. T., Ko, Y. S., Kato, H., Itoyama, Y., & Kogure, K. (2008). Influence of ischemic preconditioning on levels of nerve growth factor, brain-derived neurotrophic factor and their high-

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In the current study at the end of treatment; there was a significant increase in the serum BDNF level in the study group, while the control group showed no significant increase in the serum BDNF level. These results proved the positive effect of aerobic exercise on cognition that comes in agreement with many previous studies (Ding et al., 2006; Johnson, et al., 2003; Neeper, Gómez-Pinilla, Choi, & Cotman, 1995; Sutoo & Akiyama, 2003). Intensity and duration of aerobic exercises also was subject of debates as some studies showed that improvement in cognitive flexibility was proportional to the degree of exercise (Masley, Roetzheim, & Gualtieri, 2009). It was found that endurance training promotes brain health as it increases the size of the anterior hippocampus with 2% increase the expression of BDNF in it and this was accompanied with greater serum levels of BDNF (Erickson et al., 2011; Zoladz et al., 2008). It was proved that there was a critical threshold of rehabilitation, below which recovery will not occur, and that BDNF mediates functional recovery. That is why the use of intensive rehabilitation therapies for stroke patients was highly recommended (MacLellan et al., 2011). Ploughman et al. (2008), couldn’t prove the efficacy of intense aerobic exercises on cognitive functions. This may be explained by the fact that they performed only short duration of physiotherapy intervention and due to their small sample size (Ploughman, McCarthy, Bossé, Sullivan, & Corbett, 2008) that is why we choose the minimum period of eight weeks to reassess our patients. We also found a positive correlation between increase in serum BDNF level and improvement in ACER tests scores in our study group (G2). These results indicated that changes in BDNF level can be a biomarker for improvement of cognitive functions and consequently take part of the future cell therapy management of stroke patients (Alder, Kramer, Hoskin, & ThakkerVaria, 2012). Our study has some limitations that should be addressed in further studies: (1) the study was a pilot study with relatively a small sample size. (2) Cognitive function improvement may occur at different grades of exercise intensity, a parameter that was not utilized in this study. We acknowledge that further research to address objectively the effect of aerobic exercises on physiological and chemical biomarkers of the brain.

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6. Conclusion Aerobic exercises are considered as an effective method for improving cognitive impairment in stroke


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cognitive or upper-extremity tasks in people with chronic stroke? A randomized cross-over trial. Arch Phys Med Rehabil, 89(11), 2041-2047. Quaney, B. M., Boyd, L. A., McDowd, J. M., Zahner, L. H., He, J., Mayo, M. S., et al. (2009). Aerobic exercise improves cognition and motor function poststroke. Neurorehabil Neural Repair, 23(9), 879-885. Rand, D., Eng, J. J., Liu-Ambrose, T., & Tawashy, A. E. (2010). Feasibility of a 6-month exercise and recreation program to improve executive functioning and memory in individuals with chronic stroke. Neurorehabil Neural Repair, 24(8), 722-729. Rosenfeld, R.D., Zeni, L., Haniu, M., Talvenheimo, J., Radka, S.F., Bennett, L., et al. (1995). Purification and identification of brainderived neurotrophic factor from human serum. Protein Expr Purif, 6(4), 465-471. Sutoo, D., & Akiyama, K. (2003). Regulation of brain function by exercise. Neurobiol Dis, 13(1), 1-14. Wu, C. Y., Lin, K. C., Wolf, S. L., & Roby-Brami, A. (2012). Motor rehabilitation after stroke. Stroke Res Treat, 2012, 810706. Zoladz, J. A., Pilc, A., Majerczak, J., Grandys, M., Zapart-Bukowska, J., & Duda, K. (2008). Endurance training increases plasma brainderived neurotrophic factor concentration in young healthy men. J Physiol Pharmacol, 59(Suppl 7), 119-132.

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affinity receptors in hippocampus following forebrain ischemia. Brain Res, 1187, 1-11. MacLellan, C. L., Keough, M. B., Granter-Button, S., Chernenko, G. A., Butt, S., & Corbett, D. (2011). A critical threshold of rehabilitation involving brain-derived neurotrophic factor is required for poststroke recovery. Neurorehabil Neural Repair, 25(8), 740-748. Masley, S., Roetzheim, R., & Gualtieri, T. (2009). Aerobic exercise enhances cognitive flexibility. J Clin Psychol Med Settings, 16(2), 186-193. McAuley, E., Kramer, A. F., & Colcombe, S. J. (2004). Cardiovascular fitness and neurocognitive function in older adults: A brief review. Brain Behav Immun, 18(3), 214-220. Mioshi, E., Dawson, K., Mitchell, J., Arnold, R., & Hodges, J.R. (2006). The Addenbrooke’s Cognitive Examination Revised (ACE-R): A brief cognitive test battery for dementia screening. Int J Geriatr Psychiatry, 21(11), 1078-1085. Molteni, R., Ying, Z., & Gómez-Pinilla, F. (2002). Differential effects of acute and chronic exercise on plasticity-related genes in the rat hippocampus revealed by microarray. Eur J Neurosci, 16(6), 1107-1116. Neeper, S. A., Gómez-Pinilla, F., Choi, J., & Cotman, C. (1995). Exercise and brain neurotrophins. Nature, 373(6510), 109. Ploughman, M., McCarthy, J., Bossé, M., Sullivan, H. J., & Corbett, D. (2008). Does treadmill exercise improve performance of

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