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An investigation into the relationship between cardiorespiratory fitness, cognition and BDNF in young healthy males
Neuroscience Letters 704 (2019) 126–132
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Neuroscience Letters journal homepage: www.elsevier.com/locate/neulet
Research article
An investigation into the relationship between cardiorespiratory fitness, cognition and BDNF in young healthy males
T
⁎
Jennifer M. Fortunea, , Áine M. Kellyb,c, Ian H. Robertsonc,d, Juliette Husseye a
Academic Unit of Neurology, University of Dublin, Trinity College, Dublin 2, Ireland Department of Physiology, School of Medicine, University of Dublin, Trinity College, Dublin 2, Ireland c School of Psychology, University of Dublin, Trinity College, Dublin 2, Ireland d Trinity College Institute of Neuroscience, University of Dublin, Trinity College, Dublin 2, Ireland e Discipline of Physiotherapy, University of Dublin, Trinity College, Dublin 2, Ireland b
A R T I C LE I N FO
A B S T R A C T
Keywords: Cognitive function Brain-derived neurotrophic factor (BDNF) Cardiorespiratory fitness VO2max Human
Background: Recent investigations demonstrate that cardiorespiratory fitness may benefit brain health and plasticity with concurrent enhancements in cognitive performance; possibly via a brain-derived neurotrophic factor (BDNF)-regulated mechanism. While a number of studies have demonstrated an increase in BDNF concentration post exercise the relationship between BDNF, cardiorespiratory fitness and cognitive function requires further investigation. Objective: The present cross-sectional study assessed the association between cardiorespiratory fitness (VO2max), cognitive performance and circulating BDNF concentration. Methods: Thirty-nine healthy male volunteers (mean age 21.7 ± 0.5 years) participated. Cognitive performance was measured by reaction time on a standard detection task and accuracy in a n-back and Continuous Paired Associative Learning (CPAL) task. Cardiorespiratory fitness was assessed using a standardised graded exercise test. Plasma and serum BDNF concentrations were assayed by ELISA. Results: A significant negative correlation between VO2max and reaction time was demonstrated (p < 0.05). However VO2max was not associated with circulating BDNF concentration, or performance in the n-back and CPAL tasks (p > 0.05). Conclusions: Enhanced psychomotor speed was associated with higher cardiorespiratory fitness. In contrast to previous research no significant association between cardiorespiratory fitness and BDNF concentration was observed.
1. Introduction Over the past decade, evidence supporting fitness-induced benefits to structural and functional cognitive health in human populations has grown. Cardiorespiratory fitness is associated with the preservation of cortical integrity as well as volumetric enhancement of the hippocampus and pre-frontal regions [17,18,60]. In addition to these structural benefits, a robust positive effect of aerobic capacity on behavioural indices of executive function have been shown [19,52]. Although the neuronal mechanisms remain to be fully elucidated, recent evidence suggests brain-derived neurotrophic factor (BDNF) as a major mediator of the relationship between cardiorespiratory fitness and cognitive function. BDNF is a member of the neurotrophin family of
growth factors which promote neuronal survival and synaptic plasticity. BDNF expression in the brain, particularly the hippocampus, is increased post-exercise in rodents concomitant with enhanced learning and memory [3,24], suggesting a role for BDNF in exercise-induced cognitive enhancement through its inducement of structural and neuroplastic changes within the brain. A great deal of ambiguity exists regarding the relationship between cardiorespiratory fitness and BDNF in human subjects. Some studies indicate that increased cardiorespiratory fitness is associated with higher resting concentrations of BDNF [23,55] while others demonstrate an inverse relationship [1,14,32,48] or no association [10,56,61]. Furthermore while animal literature provides strong support for BDNF-mediated cognitive enhancement [8,41] the relationship between these factors is less clear in
Abbreviations: (BDNF), brain-derived neurotrophic factor; (ELISA), enzyme-linked immunosorbent assay; (GXT), graded exercise test; (PAR-Q), physical activity readiness questionnaire; (DET), detection task; (CPAL), Continuous Paired Associative Learning; (VO2max), maximal oxygen consumption rate ⁎ Corresponding author at: Academic Unit of Neurology, University of Dublin, Trinity College, Dublin 2, Ireland. E-mail address: [email protected] (J.M. Fortune). https://doi.org/10.1016/j.neulet.2019.03.012 Received 30 October 2018; Received in revised form 11 February 2019; Accepted 8 March 2019 Available online 09 March 2019 0304-3940/ © 2019 Published by Elsevier B.V.
Neuroscience Letters 704 (2019) 126–132
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-Tetramethylebenzidine (TMB) one solution was added (50 μl/well) and incubated in the dark at room temperature for 20 min. The reaction was stopped using 1MH2SO4 (50 μl/well). The optical density (OD) was measured at 450 nm and 540 nm using a 96-well plate reader (Synergy HT Multi Mode Microplate Reader, BioTek®Instruments, UK). The reading at 540 nm was subtracted from the reading at 450 nm to correct for optical imperfections in the plate. A standard curve was constructed and the regression equation of the curve was used to calculate the concentration of BDNF in each sample. The intra-assay and inter-assay variations were 2.3% and 4.1% respectively.
human subjects. Higher concentrations of circulating BDNF have been associated with enhanced cognitive performance [35,55]. Moreover BDNF expression is decreased in a range neurodegenerative and psychiatric diseases [21,22,29] and correlates negatively with cognitive impairment and Alzheimer’s dementia [37]. Collectively these studies indicate that BDNF may at least in part correlate positively with cognitive performance. Extant research in animal models suggests BDNF as a molecular mediator of exercise-induced cognitive enhancement. Whether an analogous association exists in human subjects remains unknown. Therefore, the aim of the present study was to further explore the relationship between cardiorespiratory fitness (VO2max), cognitive performance and resting BDNF concentrations in a young healthy population.
2.4. Cognitive testing Cognitive performance was assessed using the CogState computerised neuropsychological assessment which has demonstrated validity and sensitivity in a range of populations [15,20,26,39,46]. The CogState assessment was specifically developed to assess cognitive function across repeated measurements with minimal practice effects [20] even at short test retest intervals [12]. Four subtests from the larger CogState battery were administered: Detection Task (DET: psychomotor speed), One-back task (OBK: working memory), Two-back task (TBK: working memory) and Continuous Paired Associate Learning task (CPAL: visuospatial learning and memory). The main outcome measure for the DET task is reaction time in milliseconds which was normalised using a logarithmic base 10 (log10) transformation. The main outcome measure for the OBK and TBK tasks is the proportion of correct responses (accuracy). The main outcome for the CPAL task is total number of errors made. Practice effects were controlled for through the use of a nonscored practice assessment.
2. Materials and method 2.1. Participants Forty-one healthy male students volunteered to participate (age, BMI: 21.7 ± 0.5 yrs, 23.5 ± 0.4 kg/m2 respectively mean ± SEM). All participants were male, aged 18–29 years. Exclusion criteria included use of prescription medication, smoking and recreational drug use, a history of any orthopaedic, musculoskeletal, neurological, cardiovascular, pulmonary problems/issues and/or any other contraindications to physical activity identified by the PAR-Q. Participants were instructed to fast for three hours, refrain from caffeinated drinks for 12 h and abstain from alcohol consumption and strenuous exercise for 24 h preceding study participation. Two participants were excluded from analysis due to an incomplete blood sample data and incomplete VO2max data respectively, resulting in a final sample of 39 participants. This study was conducted in accordance with the declaration of Helsinki. All participants provided written informed consent.
2.5. Assessment of cardiorespiratory fitness Cardiorespiratory fitness was assessed by GXT performed on a motor-driven treadmill using the Bruce Protocol [5]. VO2max was determined by indirect calorimetry using a metabolic cart (Cosmed Quark CPET). Briefly the protocol began at a speed of 2.7 km.h−1 and an incline of 10% grade. The speed and incline increased by an average of 1.15 km.h-1 and 2% grade every three minutes. Prior to and following completion of the GXT a three minute warm up and cool down (2.7 km h−1, incline 0%) were completed. Exercise test termination criteria followed the recommendations of the American College of Sports Medicine [45]. Following determination of VO2max participants were divided into a high or low VO2max group (Table 1) based on the cardiorespiratory classification for men aged 20–29 [28]. Participants classified in the poor (n = 6), fair (n = 3) or good (n = 12) category were assigned the low VO2max group. Participants classified as excellent (n = 12) or superior (n = 6) were assigned the high VO2max group.
2.2. Experimental overview Participants were required to attend the Exercise Physiology Laboratory on one occasion. During the testing session a baseline blood sample was taken from all participants. Following this a battery of cognitive tasks was performed. Finally, all participants completed a graded exercise test (GXT). 2.3. Blood sampling and assays Basal serum and plasma samples were drawn from a free-flowing vein in the antecubital fossa into sterile SST™ gel and clot activator and EDTA tubes, respectively. Samples were incubated at room temperature and then centrifuged at 3000 rpm at 4 °C for 15 min. The resulting supernatant was removed and stored at −80 °C until analysis. BDNF concentrations were assayed as per manufacturer’s guidelines using a commercially available Human BDNF Duoset® ELISA development systems kit (R&D Systems Europe Oxon, UK). A 96-well plate (NUNCimmuno™ MaxiSorp™ plate; Denmark) was coated with capture antibody (2 μg.ml−1 mouse anti-human BDNF diluted in PBS (50 μl/well) and incubated overnight at room temperature. The plate was washed with wash buffer (PBS-T; 0.05% Tween®20 in PBS) using a mulitpipette and blocked with reagent diluent (1% BSA in PBS; 150 μl/well) for 1 h at room temperature. After washing, standards (recombinant human BDNF diluted in reagent diluents, top standard concentration: 1500 pg.ml−1) and samples were added in duplicate (50 μl/well) and incubated for 2 h at room temperature. The plate was washed and incubated with detection antibody (25 ng.ml−1 biotinylated mouse antihuman BDNF in reagent diluent; 50 μl/well) for 2 h at room temperature. Following this, the plate was washed and reacted with Streptavidin-HRP complex (1:200 dilution in reagent diluent; 50 μl/ well) for 20 min at room temperature. After washing,
2.6. Statistical analysis Statistical analysis were performed using SPSS version 21 (SPSS Inc; Chicago, IL, USA) with statistical significance set at p < 0.05. Data are expressed as mean ± SEM. Group n numbers are indicated in Figs. 1–4. Where n numbers differ it is due to the removal of cognitive values which did not pass integrity checks applied by the CogState software. This led to the removal of cognitive test scores in the OBK (n = 1) and Table 1 Descriptive Statistics High and Low VO2max Groups.
Low VO2max High VO2max
n
M
SEM
21 18
44.42 55.87
0.97 0.95
Data are presented as Mean ± SEM. 127
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Fig. 1. Cognitive task performance in high and low fit participants. (A) There was a significant difference in reaction time between participants with high and low levels of fitness *p < 0.05 (Low n = 21, High n = 18). VO2max score did not influence accuracy in the OBK (B) (Low n = 21, High n = 17) or TBK (C) (Low n = 20, High n = 18) task or affect error rate in the CPAL (D) task (Low n = 21, High n = 18). Statistical analysis by Mann-Whitney U test.
-0.948, p =0.361; Fig. 1C). Finally there was no statistically significant different in CPAL error rate between the high or low VO2max groups (U = 195.000, z = 0.169, p =0.878; Fig. 1D).
TBK (n = 1) and is clearly indicated. Mann-Whitney U test and Independent sample t-test were used to determine the difference in cognitive performance and BDNF concentration respectively between high and low fit participants. Spearman-rank order and Pearson-product moment correlation coefficients were used as appropriate to examine the associations between cognitive performance, BDNF concentration and cardiorespiratory fitness. Plasma BDNF concentrations were logtransformed.
3.2. BDNF concentrations in high fit and low fit participants Mean serum BDNF concentration for participants in the high (26.56 ± 3.21) and low (27.49 ± 3.01) VO2max groups were not significantly different, (t (37) = 0.212, p = 0.834; Fig. 2A). Mean plasma BDNF concentrations participants in the high (3.09 ± 0.08) and low (3.20 ± 0.09) VO2max groups were not significantly different (t (37) = 1.351, p = 0.185; Fig. 2B).
3. Results 3.1. Cognitive performance in high and low fit participants
3.3. Cardiorespiratory fitness and cognitive performance
Participants in the high VO2max group demonstrated significantly faster reaction time compared participants in the low VO2max group (U = 110.5, z=-2.217, p=0.026; Fig. 1A). There was no difference between fitness groups in accuracy on the OBK (U = 200.5, z = 0.660, p=0.523; Fig. 1B), or TBK condition of the n-back task (U = 148.0, z =
A significant negative correlation was demonstrated between VO2max and reaction time in the detection task (r=-0.319, p=0.048; Fig. 3A). No correlation was demonstrated between VO2max and
Fig. 2. Effect of High and Low VO2 max (ml.kg-1.min-1) on BDNF concentration. There was no difference in serum (A) or plasma (B) concentrations of BDNF (p > 0.05) between low and high fit participants (Low n = 21, High n = 18). Statistical analysis by Independent samples t-test. 128
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Fig. 3. Association between CRF and cognitive performance. (A) A significant negative correlation was demonstrated between VO2 max (ml.kg-1.min-1) and reaction time in the DET task (*p < .05,n = 39). No associations were demonstrated between VO2max and cognitive performance in (B) the OBK (n = 38), (C) TBK (n = 38), or (D) CPAL task (n = 39). Statistical analysis by Spearman correlation.
accuracy on the OBK (r = 0.031, p = 0.855) or TBK (r = 0.044, p = 0.792) condition of the n-back task or error rate in the CPAL task (r = 0.133, p = 0.421).
Table 2 Association between Cognitive Testing Results and BDNF concentration. S BDNF
3.4. Cardiorespiratory fitness and BDNF concentration
DET OBK TBK CPAL
No correlation was demonstrated between VO2max and mean serum (r = 0.119, p = 0.469; Fig. 4A) or plasma (r=-0.129, p = 0.434; Fig. 4B) BDNF concentration.
P BDNF
M ± SEM
r
p
r
p
2.43 ± .01 1.26 ± .01 1.28 ± .02 15.01 ± 1.92
0.050 −0.046 0.215 0.108
0.761 0.784 0.194 0.514
−0.157 0.100 0.198 −0.257
0.341 0.551 0.234 0.115
4. Discussion 3.5. Cognitive performance and BDNF concentrations
4.1. Cardiorespiratory fitness and cognitive performance
No correlation was demonstrated between plasma or serum BDNF concentration and reaction time, OBK accuracy, TBK accuracy or CPAL error rate (p > 0.05, Table 2).
In the present study participants with high VO2max scores demonstrated significantly faster reaction times than their low fit counterparts. Additionally, higher cardiorespiratory fitness was positively associated with reaction time. These results replicate cross-sectional studies in older adult cohorts which demonstrate that fit individuals
Fig. 4. Association between VO2 max and BDNF concentration. There was no association between VO2max (ml.kg-1.min-1) and serum (A) or plasma (B) BDNF concentrations (p > 0.05), n = 39; Pearson correlation. 129
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quantification of cardiorespiratory fitness using a validated protocol in combination with indirect calorimetry No correlation was demonstrated between serum and plasma BDNF concentration and cardiorespiratory fitness. These results are similar to a number of studies which failed to identify an association between these variables [10,30,34,56,59,61]. However they are in contrast to previous studies which observed a positive relationship [23,64] and others that have demonstrated a negative association [1,7,14,31,32,44,48]. To date the studies which have demonstrated a positive association have included inactive older adults [64] or clinical populations [23,55]. In these cohorts small increases in cardiorespiratory fitness may lead to increases in circulating BDNF concentrations; however in young, fit populations it is possible that these small increases are not sufficient to cause a change. One plausible explanation underlying the present results is the homogenous cardiorespiratory fitness displayed by the participants. Participants were divided into a high or low VO2max group. Participants in the high VO2max group were correctly categorised as high fit, with mean VO2max values above the 90th percentile [45]. However, in the low fit group mean VO2max values corresponded to the 50th percentile, indicating that these participants might be more correctly classified as moderately fit, rather than low-fit. It is therefore possible that the association between cardiorespiratory fitness and BDNF was attenuated, as the present sample provides little information regarding the contrasting spectrums of aerobic capacity due to the relatively small differences in fitness levels between groups. In addition to its neurotrophic actions increasing evidence suggests a regulatory role for BDNF in body weight maintenance and energy homeostasis. BDNF correlates positively with BMI [40,42]. Furthermore BDNF expression is elevated in response to metabolic conditions such as diabetes [54]. This upregulation of BDNF likely represents a compensatory response to ameliorate the deleterious effects of abnormal glucose regulation on metabolism [43]. Participants presented with healthy body composition and therefore BDNF upregulation as a metabolic compensatory mechanism was unlikely to be present in this population. Additionally, all participants were well educated (17.23 ± 0.31 years) and close to the age when executive function is thought to be highest [63]. It is possible that the young cognitively intact brain has less need for BDNF regulated mechanisms to improve function compared to clinical or elderly populations who are at risk of cognitive decline. Taken together it is possible that in healthy adults less BDNF is needed for the maintenance of both metabolic and cognitive behaviours and this may underlie the lack of association presented in this study.
consistently outperform their low fit counterparts on reaction and movement times [9,53]; thus providing evidence that the positive assocation between and pyschomotor speed is apparent across a range of age groups. In contrast, no difference in cognitive performance was demonstrated between high and low fit participants and no correlation was observed between cardiorespiratory fitness and cognitive performance in the OBK, TBK or CPAL tasks. These tasks measure working memory, and visual learning and memory respectively which are components of executive control. These results contrast findings in a meta-analysis of older adults which demonstrated a positive association between executive control and cardiorespiratory fitness [11]. While decrements in cognitive function have been demonstrated in the third and fourth decade of healthy, educated adults [47], age-related cognitive decline is typically not apparent until after the sixth decade [49]. Decreased cognitive performance may already be apparent in older adults and therefore smaller increments in cardiorespiratory fitness may have a larger beneficial effect on executive control. In younger cohorts, in the absence of cognitive or structural impairment it is possible that small increases in cardiorespiratory fitness are not sufficient to lead to cognitive change. Relative to the aging literature comparatively fewer studies have examined the relationship between cardiorespiratory fitness and cognitive function in young adults. Existing research in these cohorts vary greatly in sample size, neuropsychological measure and fitness assessment utilized which limits definitive conclusions being drawn. While positive effects have been observed [2,31,38,51] others have failed to find any association [27,50] or have observed a relationship on some measures only [38]. While positive findings were demonstrated for reaction time in the present study, we failed to observe an association between cardiorespiratory fitness and performance on the n-back task. Our findings are inconsistent with recent research which examined the association between working memory and cardiorespiratory fitness in college-aged individuals [31,51]. Larger sample sizes and a greater diversity of fitness levels may have contributed to our equivocal findings and highlight the importance of including a spectrum of cardiorespiratory fitness levels in future research. A further potential explanation for these observations is that the cognitive measures utilised may not have been sensitive enough to detect change. In younger cohorts increased efficiency of brain functioning as a result of higher cardiorespiratory fitness has been demonstrated without associated improvements in behavioural performance [33,57]. This suggests that the effects of cardiorespiratory fitness on behavioral measures of cognitive performance may only emerge in high-functioning groups when the task is extremely difficult [58]. Increasing the task difficulty in younger cohorts may reduce the chances of ceiling effect in future studies. Furthermore, neuroimaging techniques may allow detection of exercise induced change at the cortical level that is not readily observable at the behavioral level.
4.3. BDNF and cognitive performance No correlations were demonstrated between cognitive task performance and BDNF concentration. To date the strongest evidence to support the putative role of BDNF in cognitive performance has been obtained using animal models. Animals administered exogenous neural injections of BDNF demonstrate improvements in spatial learning and memory [8] and object recognition learning [25]. Conversely in animals where the endogenous expression of hippocampal BDNF is blocked declines in cognitive performance are noted [41]. Collectively these studies demonstrate the importance of BDNF for cognitive performance in animal models. To date very limited literature exists relating BDNF to cognition in humans. Positive links between peripheral BDNF concentration and cognitive performance have been demonstrated [16,55].Furthermore associations have been shown between BDNF concentrations and severity of cognitive decline in Alzheimer’s disease. [36]. Collectively this literature provides preliminary support for the importance of BDNF for cognitive performance and brain health; however, these findings were not replicated in the current study. More research is needed to further elucidate the link between these factors.
4.2. BDNF and cardiorespiratory fitness Mean serum and plasma BDNF concentration were similar in participants classified as having a high versus low level of cardiorespiratory fitness. These results are similar to previous findings which have demonstrated no significant difference in circulating BDNF concentration between active and inactive participants [43,59,62]. However they are in contrast to results from studies that have demonstrated higher [4,13,65] and lower [1,6,43] BDNF concentrations in high fit participants. A possible explanation for this discrepancy is that existing literature is limited by the use of subjective measures to quantify fitness. These methods are open to reporting bias and may inadvertently reflect the influence of other variables on cognition such as a healthy lifestyle. Objective measurement has previously been highlighted as necessary to advance research into the area of physical activity and BDNF [43]. A strength of the present investigation was the 130
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4.4. Limitations
[11] S. Colcombe, A.F. Kramer, Fitness effects on the cognitive function of older adults: a meta-analytic study, Psychol. Sci. 14 (2003) 125–130. [12] A. Collie, P. Maruff, D.G. Darby, M. McStephen, The effects of practice on the cognitive test performance of neurologically normal individuals assessed at brief test-retest intervals, J. Int. Neuropsychol. Soc. 9 (2003) 419–428. [13] P.R. Correia, F.A. Scorza, S. Gomes da Silva, A. Pansani, M. Toscano-Silva, A.C. de Almeida, R.M. Arida, Increased basal plasma brain-derived neurotrophic factor levels in sprint runners, Neurosci. Bull. 27 (2011) 325–329. [14] J. Currie, R. Ramsbottom, H. Ludlow, A. Nevill, M. Gilder, Cardio-respiratory fitness, habitual physical activity and serum brain derived neurotrophic factor (BDNF) in men and women, Neurosci. Lett. 451 (2009) 152–155. [15] L.A. Cysique, P. Maruff, D. Darby, B.J. Brew, The assessment of cognitive function in advanced HIV-1 infection and AIDS dementia complex using a new computerised cognitive test battery, Arch. Clin. Neuropsychol. 21 (2006) 185–194. [16] K.I. Erickson, R.S. Prakash, M.W. Voss, L. Chaddock, S. Heo, M. McLaren, B.D. Pence, S.A. Martin, V.J. Vieira, J.A. Woods, E. McAuley, A.F. Kramer, Brainderived neurotrophic factor is associated with age-related decline in hippocampal volume, J. Neurosci. 30 (2010) 5368–5375. [17] K.I. Erickson, R.S. Prakash, M.W. Voss, L. Chaddock, L. Hu, K.S. Morris, S.M. White, T.R. Wojcicki, E. McAuley, A.F. Kramer, Aerobic fitness is associated with hippocampal volume in elderly humans, Hippocampus 19 (2009) 1030–1039. [18] K.I. Erickson, M.W. Voss, R.S. Prakash, C. Basak, A. Szabo, L. Chaddock, J.S. Kim, S. Heo, H. Alves, S.M. White, T.R. Wojcicki, E. Mailey, V.J. Vieira, S.A. Martin, B.D. Pence, J.A. Woods, E. McAuley, A.F. Kramer, Exercise training increases size of hippocampus and improves memory, Proc. Natl. Acad. Sci. U. S. A. 108 (2011) 3017–3022. [19] J.L. Etnier, W. Salazar, D.M. Lander, S.J. Petruzzello, M. Han, P. Nowell, The influence of physical fitness and exercise upon cognitive funtioning: a meta-analysis, J. Sport Exerc. Psychol. 19 (1997) 249–277. [20] M.G. Falleti, P. Maruff, A. Collie, D.G. Darby, Practice effects associated with the repeated assessment of cognitive function using the CogState battery at 10-minute, one week and one month test-retest intervals, J. Clin. Exp. Neuropsychol. 28 (2006) 1095–1112. [21] G. Favalli, J. Li, P. Belmonte-de-Abreu, A.H. Wong, Z.J. Daskalakis, The role of BDNF in the pathophysiology and treatment of schizophrenia, J. Psychiatr. Res. 46 (2012) 1–11. [22] I. Ferrer, E. Goutan, C. Marin, M.J. Rey, T. Ribalta, Brain-derived neurotrophic factor in Huntington disease, Brain Res. 866 (2000) 257–261. [23] A. Fukushima, S. Kinugawa, T. Homma, Y. Masaki, T. Furihata, T. Yokota, S. Matsushima, T. Abe, T. Suga, S. Takada, T. Kadoguchi, R. Katsuyama, K. Oba, K. Okita, H. Tsutsui, Decreased serum brain-derived neurotrophic factor levels are correlated with exercise intolerance in patients with heart failure, Int. J. Cardiol. 168 (2013) e142–144. [24] F. Gomez-Pinilla, S. Vaynman, Z. Ying, Brain-derived neurotrophic factor functions as a metabotrophin to mediate the effects of exercise on cognition, Eur. J. Neurosci. 28 (2008) 2278–2287. [25] E.W. Griffin, R.G. Bechara, A.M. Birch, A.M. Kelly, Exercise enhances hippocampaldependent learning in the rat: evidence for a BDNF-related mechanism, Hippocampus 19 (2009) 973–980. [26] D. Hammers, E. Spurgeon, K. Ryan, C. Persad, N. Barbas, J. Heidebrink, D. Darby, B. Giordani, Validity of a brief computerized cognitive screening test in dementia, J. Geriatr. Psychiatry Neurol. 25 (2012) 89–99. [27] S.M. Hayes, D.E. Forman, M. Verfaellie, Cardiorespiratory fitness is associated with cognitive performance in older but not younger adults, J. Gerontol. Ser. B Psychol. Sci. Social Sci. 71 (2016) 474–482. [28] V.G. Heyward, Advanced Fitness Assessment and Exercise Prescription United States of America, (2014). [29] D.W. Howells, M.J. Porritt, J.Y. Wong, P.E. Batchelor, R. Kalnins, A.J. Hughes, G.A. Donnan, Reduced BDNF mRNA expression in the Parkinson’s disease substantia nigra, Exp. Neurol. 166 (2000) 127–135. [30] J. Hwang, R.M. Brothers, D.M. Castelli, E.M. Glowacki, Y.T. Chen, M.M. Salinas, J. Kim, Y. Jung, H.G. Calvert, Acute high-intensity exercise-induced cognitive enhancement and brain-derived neurotrophic factor in young, healthy adults, Neurosci. Lett. 630 (2016) 247–253. [31] J. Hwang, D.M. Castelli, F. Gonzalez-Lima, The positive cognitive impact of aerobic fitness is associated with peripheral inflammatory and brain-derived neurotrophic biomarkers in young adults, Physiol. Behav. 179 (2017) 75–89. [32] S.H. Jung, J. Kim, J.M. Davis, S.N. Blair, H.C. Cho, Association among basal serum BDNF, cardiorespiratory fitness and cardiovascular disease risk factors in untrained healthy Korean men, Eur. J. Appl. Physiol. 111 (2011) 303–311. [33] K. Kamijo, K.C. O’Leary, M.B. Pontifex, J.R. Themanson, C.H. Hillman, The relation of aerobic fitness to neuroelectric indices of cognitive and motor task preparation, Psychophysiology 47 (2010) 814–821. [34] H. Khalil, M.A. Alomari, O. Khabour, A. Al-Hieshan, J.A. Bajwa, The association between physical activity with cognitive function and brain-derived neurotrophic factor in people with Parkinson’s disease: a pilot study, J. Aging Phys. Act. 25 (2017) 646–652. [35] P. Komulainen, M. Pedersen, T. Hänninen, H. Bruunsgaard, T.A. Lakka, M. Kivipelto, M. Hassinen, T.H. Rauramaa, B.K. Pedersen, R. Rauramaa, BDNF is a novel marker of cognitive function in ageing women: the DR’s EXTRA study, Neurobiol. Learn. Mem. 90 (2008) 596–603. [36] C. Laske, K. Stellos, N. Hoffmann, E. Stransky, G. Straten, G.W. Eschweiler, T. Leyhe, Higher BDNF serum levels predict slower cognitive decline in Alzheimer’s disease patients, Int. J. Neuropsychopharmacol. 14 (2011) 399–404. [37] C. Laske, E. Stransky, T. Leyhe, G.W. Eschweiler, A. Wittorf, E. Richartz, M. Bartels, G. Buchkremer, K. Schott, Stage-dependent BDNF serum concentrations in
Limitations of the present study include the small sample size and volunteer participant group which is subject to self-selection bias. The association between cardiorespiratory fitness and psychomotor speed does not imply any causal relationship. Moreover, any directionally of causation cannot be inferred. While cardiorespiratory fitness may improve or preserve psychomotor speed, superior cognitive function may lead individuals to partake in increased levels of aerobic training. Preexisting activity levels were not controlled and as a result a limited spectrum of aerobic capacity is included. To accommodate for this limitation future projects should aim to study a population with diverse levels of cardiorespiratory fitness in order to elucidate the relationship between BDNF, cardiorespiratory fitness and cognition. It is more likely that large differences in physical fitness will reveal a difference in cognitive aptitude. 5. Conclusion In conclusion the present study demonstrates a significant negative correlation between VO2max and reaction time. Mean BDNF concentration was not significantly different between participants with high or low VO2max scores and did not correlate with cardiorespiratory fitness. Furthermore, no correlation was demonstrated between BDNF and cognitive performance. Future studies examining this relationship in diverse populations including older adults and clinical populations at risk of cognitive decline are needed in order to yield further insight into the interactive relationship between BDNF, cognitive function and cardiorespiratory fitness. Funding This research did not receive any specific grant from funding agencies in the public, commercial or not for profit sector. Ethical approval The experimental protocol was approved by the Ethics Committee for Research Involving Human Participants, Faculty of Health Sciences, Trinity College Dublin (Ethics Ref 201009). References [1] P. Babaei, A. Damirchi, M. Mehdipoor, B.S. Tehrani, Long term habitual exercise is associated with lower resting level of serum BDNF, Neurosci. Lett. 566 (2014) 304–308. [2] C.L. Baym, N.A. Khan, A. Pence, L.B. Raine, C.H. Hillman, N.J. Cohen, Aerobic fitness predicts relational memory but not item memory performance in healthy young adults, J. Cogn. Neurosci. 26 (2014) 2645–2652. [3] R.G. Bechara, A.M. Kelly, Exercise improves object recognition memory and induces BDNF expression and cell proliferation in cognitively enriched rats, Behav. Brain Res. 245 (2013) 96–100. [4] M. Belviranli, N. Okudan, B. Kabak, M. Erdogan, M. Karanfilci, The relationship between brain-derived neurotrophic factor, irisin and cognitive skills of endurance athletes, Phys. Sportsmed. 44 (2016) 290–296. [5] R.A. Bruce, J.R. Blackmon, J.W. Jones, G. Strait, Exercising testing in adult normal subjects and cardiac patients, Pediatrics 32 (Suppl) (1963) 742–756. [6] K.L. Chan, K.Y. Tong, S.P. Yip, Relationship of serum brain-derived neurotrophic factor (BDNF) and health-related lifestyle in healthy human subjects, Neurosci. Lett. 447 (2008) 124–128. [7] H.C. Cho, J. Kim, S. Kim, Y.H. Son, N. Lee, S.H. Jung, The concentrations of serum, plasma and platelet BDNF are all increased by treadmill VO(2)max performance in healthy college men, Neurosci. Lett. 519 (2012) 78–83. [8] F. Cirulli, A. Berry, F. Chiarotti, E. Alleva, Intrahippocampal administration of BDNF in adult rats affects short-term behavioral plasticity in the Morris water maze and performance in the elevated plus-maze, Hippocampus 14 (2004) 802–807. [9] L. Clarkson-Smith, A.A. Hartley, Relationships between physical exercise and cognitive abilities in older adults, Psychol. Aging 4 (1989) 183–189. [10] F.Gd.M. Coelho, T.M. Vital, A.M. Stein, F.J. Arantes, A.V. Rueda, R. Camarini, E. Teodorov, R.F. Santos-Galduróz, Acute aerobic exercise increases brain-derived neurotrophic factor levels in elderly with Alzheimer’s disease, J. Alzheimer Dis. 39 (2014) 401–408.
131
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J.M. Fortune, et al.
Sports Exerc. 48 (2016) 1994–2002. [52] P.J. Smith, J.A. Blumenthal, B.M. Hoffman, H. Cooper, T.A. Strauman, K. WelshBohmer, J.N. Browndyke, A. Sherwood, Aerobic exercise and neurocognitive performance: a meta-analytic review of randomized controlled trials, Psychosom. Med. 72 (2010) 239–252. [53] W.W. Spirduso, Reaction and movement time as a function of age and physical activity level, J. Gerontol. 30 (1975) 435–440. [54] M. Suwa, H. Kishimoto, Y. Nofuji, H. Nakano, H. Sasaki, Z. Radak, S. Kumagai, Serum brain-derived neurotrophic factor level is increased and associated with obesity in newly diagnosed female patients with type 2 diabetes mellitus, Metabolism 55 (2006) 852–857. [55] W. Swardfager, N. Herrmann, S. Marzolini, M. Saleem, P. Shammi, P.I. Oh, P.R. Albert, M. Daigle, A. Kiss, K.L. Lanctot, Brain derived neurotrophic factor, cardiopulmonary fitness and cognition in patients with coronary artery disease, Brain Behav. Immun. 25 (2011) 1264–1271. [56] D.L. Swift, N.M. Johannsen, V.H. Myers, C.P. Earnest, J.A.J. Smits, S.N. Blair, T.S. Church, The effect of exercise training modality on serum brain derived neurotrophic factor levels in individuals with type 2 diabetes, PLoS One 7 (2012). [57] J.R. Themanson, C.H. Hillman, Cardiorespiratory fitness and acute aerobic exercise effects on neuroelectric and behavioral measures of action monitoring, Neuroscience 141 (2006) 757–767. [58] M.W. Voss, L.S. Nagamatsu, T. Liu-Ambrose, A.F. Kramer, Exercise, brain, and cognition across the life span, J. Appl. Physiol. 111 (2011) 1505–1513. [59] A. Waschbisch, I. Wenny, A. Tallner, S. Schwab, K. Pfeifer, M. Maurer, Physical activity in multiple sclerosis: a comparative study of vitamin D, brain-derived neurotrophic factor and regulatory T cell populations, Eur. Neurol. 68 (2012) 122–128. [60] A.M. Weinstein, M.W. Voss, R.S. Prakash, L. Chaddock, A. Szabo, S.M. White, T.R. Wojcicki, E. Mailey, E. McAuley, A.F. Kramer, K.I. Erickson, The association between aerobic fitness and executive function is mediated by prefrontal cortex volume, Brain Behav. Immun. 26 (2012) 811–819. [61] A.S. Whiteman, D.E. Young, X. He, T.C. Chen, R.C. Wagenaar, C.E. Stern, K. Schon, Interaction between serum BDNF and aerobic fitness predicts recognition memory in healthy young adults, Behav. Brain Res. 259 (2014) 302–312. [62] R. Winker, I. Lukas, T. Perkmann, H. Haslacher, E. Ponocny, J. Lehrner, D. Tscholakoff, P. Dal-Bianco, Cognitive function in elderly marathon runners: cross-sectional data from the marathon trial (APSOEM), Wien. Klin. Wochenschr. 122 (2010) 704–716. [63] P.D. Zelazo, F.I. Craik, L. Booth, Executive function across the life span, Acta Psychol. 115 (2004) 167–183. [64] A. Zembron-Lacny, W. Dziubek, M. Rynkiewicz, B. Morawin, M. Wozniewski, Peripheral brain-derived neurotrophic factor is related to cardiovascular risk factors in active and inactive elderly men, Braz. J. Med. Biol. Res. 49 (2016). [65] J.A. Zoladz, A. Pilc, J. Majerczak, M. Grandys, J. Zapart-Bukowska, K. Duda, Endurance training increases plasma brain-derived neurotrophic factor concentration in young healthy men, J. Physiol. Pharmacol. 59 (Suppl 7) (2008) 119–132.
Alzheimer’s disease, J. Neural Transm. 113 (2006) 1217–1224. [38] P.D. Loprinzi, C.J. Kane, Exercise and cognitive function: a randomized controlled trial examining acute exercise and free-living physical activity and sedentary effects, Mayo Clin. Proc. 90 (2015) 450–460. [39] P. Maruff, E. Thomas, L. Cysique, B. Brew, A. Collie, P. Snyder, R.H. Pietrzak, Validity of the CogState brief battery: relationship to standardized tests and sensitivity to cognitive impairment in mild traumatic brain injury, schizophrenia, and AIDS dementia complex, Arch. Clin. Neuropsychol. 24 (2009) 165–178. [40] P. Monteleone, M. Fabrazzo, V. Martiadis, C. Serritella, M. Pannuto, M. Maj, Circulating brain-derived neurotrophic factor is decreased in women with anorexia and bulimia nervosa but not in women with binge-eating disorder: relationships to co-morbid depression, psychopathology and hormonal variables, Psychol. Med. 35 (2005) 897–905. [41] J.S. Mu, W.P. Li, Z.B. Yao, X.F. Zhou, Deprivation of endogenous brain-derived neurotrophic factor results in impairment of spatial learning and memory in adult rats, Brain Res. 835 (1999) 259–265. [42] M. Nakazato, K. Hashimoto, E. Shimizu, C. Kumakiri, H. Koizumi, N. Okamura, M. Mitsumori, N. Komatsu, M. Iyo, Decreased levels of serum brain-derived neurotrophic factor in female patients with eating disorders, Biol. Psychiatry 54 (2003) 485–490. [43] Y. Nofuji, M. Suwa, Y. Moriyama, H. Nakano, A. Ichimiya, R. Nishichi, H. Sasaki, Z. Radak, S. Kumagai, Decreased serum brain-derived neurotrophic factor in trained men, Neurosci. Lett. 437 (2008) 29–32. [44] N.H. Pedersen, J. Tarp, L.B. Andersen, A.K. Gejl, T. Huang, L. Peijs, A. Bugge, The association between serum brain-derived neurotrophic factor and a cluster of cardiovascular risk factors in adolescents: the CHAMPS-study DK, PLoS One 12 (2017) e0186384. [45] S.L. Pescatello, ACSM’s Guidelines for Exercise Testing and Prescription, Wolters Kluwer/Lippincott Williams & Wilkins Health, Philadelphia, USA, 2014. [46] R.H. Pietrzak, J. Olver, T. Norman, D. Piskulic, P. Maruff, P.J. Snyder, A comparison of the CogState schizophrenia battery and the measurement and treatment research to improve cognition in schizophrenia (MATRICS) battery in assessing cognitive impairment in chronic schizophrenia, J. Clin. Exp. Neuropsychol. 31 (2009) 848–859. [47] T.A. Salthouse, When does age-related cognitive decline begin? Neurobiol. Aging 30 (2009) 507–514. [48] P. Scalzo, A. Kummer, T.L. Bretas, F. Cardoso, A.L. Teixeira, Serum levels of brainderived neurotrophic factor correlate with motor impairment in Parkinson’s disease, J. Neurol. 257 (2010) 540–545. [49] K.W. Schaie, S.L. Willis, G.I. Caskie, The Seattle longitudinal study: relationship between personality and cognition, Neuropsychol. Dev. Cogn. B Aging Neuropsychol. Cogn. 11 (2004) 304–324. [50] J.L. Scisco, P.A. Leynes, J. Kang, Cardiovascular fitness and executive control during task-switching: an ERP study, Int. J. Psychophysiol. 69 (2008) 52–60. [51] S.P. Scott, D.E.S. MJ, K. Koehler, D.L. Petkus, L.E. Murray-Kolb, Cardiorespiratory fitness is associated with better executive function in young women, Med. Sci.
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Neuroscience Letters journal homepage: www.elsevier.com/locate/neulet
Research article
An investigation into the relationship between cardiorespiratory fitness, cognition and BDNF in young healthy males
T
⁎
Jennifer M. Fortunea, , Áine M. Kellyb,c, Ian H. Robertsonc,d, Juliette Husseye a
Academic Unit of Neurology, University of Dublin, Trinity College, Dublin 2, Ireland Department of Physiology, School of Medicine, University of Dublin, Trinity College, Dublin 2, Ireland c School of Psychology, University of Dublin, Trinity College, Dublin 2, Ireland d Trinity College Institute of Neuroscience, University of Dublin, Trinity College, Dublin 2, Ireland e Discipline of Physiotherapy, University of Dublin, Trinity College, Dublin 2, Ireland b
A R T I C LE I N FO
A B S T R A C T
Keywords: Cognitive function Brain-derived neurotrophic factor (BDNF) Cardiorespiratory fitness VO2max Human
Background: Recent investigations demonstrate that cardiorespiratory fitness may benefit brain health and plasticity with concurrent enhancements in cognitive performance; possibly via a brain-derived neurotrophic factor (BDNF)-regulated mechanism. While a number of studies have demonstrated an increase in BDNF concentration post exercise the relationship between BDNF, cardiorespiratory fitness and cognitive function requires further investigation. Objective: The present cross-sectional study assessed the association between cardiorespiratory fitness (VO2max), cognitive performance and circulating BDNF concentration. Methods: Thirty-nine healthy male volunteers (mean age 21.7 ± 0.5 years) participated. Cognitive performance was measured by reaction time on a standard detection task and accuracy in a n-back and Continuous Paired Associative Learning (CPAL) task. Cardiorespiratory fitness was assessed using a standardised graded exercise test. Plasma and serum BDNF concentrations were assayed by ELISA. Results: A significant negative correlation between VO2max and reaction time was demonstrated (p < 0.05). However VO2max was not associated with circulating BDNF concentration, or performance in the n-back and CPAL tasks (p > 0.05). Conclusions: Enhanced psychomotor speed was associated with higher cardiorespiratory fitness. In contrast to previous research no significant association between cardiorespiratory fitness and BDNF concentration was observed.
1. Introduction Over the past decade, evidence supporting fitness-induced benefits to structural and functional cognitive health in human populations has grown. Cardiorespiratory fitness is associated with the preservation of cortical integrity as well as volumetric enhancement of the hippocampus and pre-frontal regions [17,18,60]. In addition to these structural benefits, a robust positive effect of aerobic capacity on behavioural indices of executive function have been shown [19,52]. Although the neuronal mechanisms remain to be fully elucidated, recent evidence suggests brain-derived neurotrophic factor (BDNF) as a major mediator of the relationship between cardiorespiratory fitness and cognitive function. BDNF is a member of the neurotrophin family of
growth factors which promote neuronal survival and synaptic plasticity. BDNF expression in the brain, particularly the hippocampus, is increased post-exercise in rodents concomitant with enhanced learning and memory [3,24], suggesting a role for BDNF in exercise-induced cognitive enhancement through its inducement of structural and neuroplastic changes within the brain. A great deal of ambiguity exists regarding the relationship between cardiorespiratory fitness and BDNF in human subjects. Some studies indicate that increased cardiorespiratory fitness is associated with higher resting concentrations of BDNF [23,55] while others demonstrate an inverse relationship [1,14,32,48] or no association [10,56,61]. Furthermore while animal literature provides strong support for BDNF-mediated cognitive enhancement [8,41] the relationship between these factors is less clear in
Abbreviations: (BDNF), brain-derived neurotrophic factor; (ELISA), enzyme-linked immunosorbent assay; (GXT), graded exercise test; (PAR-Q), physical activity readiness questionnaire; (DET), detection task; (CPAL), Continuous Paired Associative Learning; (VO2max), maximal oxygen consumption rate ⁎ Corresponding author at: Academic Unit of Neurology, University of Dublin, Trinity College, Dublin 2, Ireland. E-mail address: [email protected] (J.M. Fortune). https://doi.org/10.1016/j.neulet.2019.03.012 Received 30 October 2018; Received in revised form 11 February 2019; Accepted 8 March 2019 Available online 09 March 2019 0304-3940/ © 2019 Published by Elsevier B.V.
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-Tetramethylebenzidine (TMB) one solution was added (50 μl/well) and incubated in the dark at room temperature for 20 min. The reaction was stopped using 1MH2SO4 (50 μl/well). The optical density (OD) was measured at 450 nm and 540 nm using a 96-well plate reader (Synergy HT Multi Mode Microplate Reader, BioTek®Instruments, UK). The reading at 540 nm was subtracted from the reading at 450 nm to correct for optical imperfections in the plate. A standard curve was constructed and the regression equation of the curve was used to calculate the concentration of BDNF in each sample. The intra-assay and inter-assay variations were 2.3% and 4.1% respectively.
human subjects. Higher concentrations of circulating BDNF have been associated with enhanced cognitive performance [35,55]. Moreover BDNF expression is decreased in a range neurodegenerative and psychiatric diseases [21,22,29] and correlates negatively with cognitive impairment and Alzheimer’s dementia [37]. Collectively these studies indicate that BDNF may at least in part correlate positively with cognitive performance. Extant research in animal models suggests BDNF as a molecular mediator of exercise-induced cognitive enhancement. Whether an analogous association exists in human subjects remains unknown. Therefore, the aim of the present study was to further explore the relationship between cardiorespiratory fitness (VO2max), cognitive performance and resting BDNF concentrations in a young healthy population.
2.4. Cognitive testing Cognitive performance was assessed using the CogState computerised neuropsychological assessment which has demonstrated validity and sensitivity in a range of populations [15,20,26,39,46]. The CogState assessment was specifically developed to assess cognitive function across repeated measurements with minimal practice effects [20] even at short test retest intervals [12]. Four subtests from the larger CogState battery were administered: Detection Task (DET: psychomotor speed), One-back task (OBK: working memory), Two-back task (TBK: working memory) and Continuous Paired Associate Learning task (CPAL: visuospatial learning and memory). The main outcome measure for the DET task is reaction time in milliseconds which was normalised using a logarithmic base 10 (log10) transformation. The main outcome measure for the OBK and TBK tasks is the proportion of correct responses (accuracy). The main outcome for the CPAL task is total number of errors made. Practice effects were controlled for through the use of a nonscored practice assessment.
2. Materials and method 2.1. Participants Forty-one healthy male students volunteered to participate (age, BMI: 21.7 ± 0.5 yrs, 23.5 ± 0.4 kg/m2 respectively mean ± SEM). All participants were male, aged 18–29 years. Exclusion criteria included use of prescription medication, smoking and recreational drug use, a history of any orthopaedic, musculoskeletal, neurological, cardiovascular, pulmonary problems/issues and/or any other contraindications to physical activity identified by the PAR-Q. Participants were instructed to fast for three hours, refrain from caffeinated drinks for 12 h and abstain from alcohol consumption and strenuous exercise for 24 h preceding study participation. Two participants were excluded from analysis due to an incomplete blood sample data and incomplete VO2max data respectively, resulting in a final sample of 39 participants. This study was conducted in accordance with the declaration of Helsinki. All participants provided written informed consent.
2.5. Assessment of cardiorespiratory fitness Cardiorespiratory fitness was assessed by GXT performed on a motor-driven treadmill using the Bruce Protocol [5]. VO2max was determined by indirect calorimetry using a metabolic cart (Cosmed Quark CPET). Briefly the protocol began at a speed of 2.7 km.h−1 and an incline of 10% grade. The speed and incline increased by an average of 1.15 km.h-1 and 2% grade every three minutes. Prior to and following completion of the GXT a three minute warm up and cool down (2.7 km h−1, incline 0%) were completed. Exercise test termination criteria followed the recommendations of the American College of Sports Medicine [45]. Following determination of VO2max participants were divided into a high or low VO2max group (Table 1) based on the cardiorespiratory classification for men aged 20–29 [28]. Participants classified in the poor (n = 6), fair (n = 3) or good (n = 12) category were assigned the low VO2max group. Participants classified as excellent (n = 12) or superior (n = 6) were assigned the high VO2max group.
2.2. Experimental overview Participants were required to attend the Exercise Physiology Laboratory on one occasion. During the testing session a baseline blood sample was taken from all participants. Following this a battery of cognitive tasks was performed. Finally, all participants completed a graded exercise test (GXT). 2.3. Blood sampling and assays Basal serum and plasma samples were drawn from a free-flowing vein in the antecubital fossa into sterile SST™ gel and clot activator and EDTA tubes, respectively. Samples were incubated at room temperature and then centrifuged at 3000 rpm at 4 °C for 15 min. The resulting supernatant was removed and stored at −80 °C until analysis. BDNF concentrations were assayed as per manufacturer’s guidelines using a commercially available Human BDNF Duoset® ELISA development systems kit (R&D Systems Europe Oxon, UK). A 96-well plate (NUNCimmuno™ MaxiSorp™ plate; Denmark) was coated with capture antibody (2 μg.ml−1 mouse anti-human BDNF diluted in PBS (50 μl/well) and incubated overnight at room temperature. The plate was washed with wash buffer (PBS-T; 0.05% Tween®20 in PBS) using a mulitpipette and blocked with reagent diluent (1% BSA in PBS; 150 μl/well) for 1 h at room temperature. After washing, standards (recombinant human BDNF diluted in reagent diluents, top standard concentration: 1500 pg.ml−1) and samples were added in duplicate (50 μl/well) and incubated for 2 h at room temperature. The plate was washed and incubated with detection antibody (25 ng.ml−1 biotinylated mouse antihuman BDNF in reagent diluent; 50 μl/well) for 2 h at room temperature. Following this, the plate was washed and reacted with Streptavidin-HRP complex (1:200 dilution in reagent diluent; 50 μl/ well) for 20 min at room temperature. After washing,
2.6. Statistical analysis Statistical analysis were performed using SPSS version 21 (SPSS Inc; Chicago, IL, USA) with statistical significance set at p < 0.05. Data are expressed as mean ± SEM. Group n numbers are indicated in Figs. 1–4. Where n numbers differ it is due to the removal of cognitive values which did not pass integrity checks applied by the CogState software. This led to the removal of cognitive test scores in the OBK (n = 1) and Table 1 Descriptive Statistics High and Low VO2max Groups.
Low VO2max High VO2max
n
M
SEM
21 18
44.42 55.87
0.97 0.95
Data are presented as Mean ± SEM. 127
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Fig. 1. Cognitive task performance in high and low fit participants. (A) There was a significant difference in reaction time between participants with high and low levels of fitness *p < 0.05 (Low n = 21, High n = 18). VO2max score did not influence accuracy in the OBK (B) (Low n = 21, High n = 17) or TBK (C) (Low n = 20, High n = 18) task or affect error rate in the CPAL (D) task (Low n = 21, High n = 18). Statistical analysis by Mann-Whitney U test.
-0.948, p =0.361; Fig. 1C). Finally there was no statistically significant different in CPAL error rate between the high or low VO2max groups (U = 195.000, z = 0.169, p =0.878; Fig. 1D).
TBK (n = 1) and is clearly indicated. Mann-Whitney U test and Independent sample t-test were used to determine the difference in cognitive performance and BDNF concentration respectively between high and low fit participants. Spearman-rank order and Pearson-product moment correlation coefficients were used as appropriate to examine the associations between cognitive performance, BDNF concentration and cardiorespiratory fitness. Plasma BDNF concentrations were logtransformed.
3.2. BDNF concentrations in high fit and low fit participants Mean serum BDNF concentration for participants in the high (26.56 ± 3.21) and low (27.49 ± 3.01) VO2max groups were not significantly different, (t (37) = 0.212, p = 0.834; Fig. 2A). Mean plasma BDNF concentrations participants in the high (3.09 ± 0.08) and low (3.20 ± 0.09) VO2max groups were not significantly different (t (37) = 1.351, p = 0.185; Fig. 2B).
3. Results 3.1. Cognitive performance in high and low fit participants
3.3. Cardiorespiratory fitness and cognitive performance
Participants in the high VO2max group demonstrated significantly faster reaction time compared participants in the low VO2max group (U = 110.5, z=-2.217, p=0.026; Fig. 1A). There was no difference between fitness groups in accuracy on the OBK (U = 200.5, z = 0.660, p=0.523; Fig. 1B), or TBK condition of the n-back task (U = 148.0, z =
A significant negative correlation was demonstrated between VO2max and reaction time in the detection task (r=-0.319, p=0.048; Fig. 3A). No correlation was demonstrated between VO2max and
Fig. 2. Effect of High and Low VO2 max (ml.kg-1.min-1) on BDNF concentration. There was no difference in serum (A) or plasma (B) concentrations of BDNF (p > 0.05) between low and high fit participants (Low n = 21, High n = 18). Statistical analysis by Independent samples t-test. 128
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Fig. 3. Association between CRF and cognitive performance. (A) A significant negative correlation was demonstrated between VO2 max (ml.kg-1.min-1) and reaction time in the DET task (*p < .05,n = 39). No associations were demonstrated between VO2max and cognitive performance in (B) the OBK (n = 38), (C) TBK (n = 38), or (D) CPAL task (n = 39). Statistical analysis by Spearman correlation.
accuracy on the OBK (r = 0.031, p = 0.855) or TBK (r = 0.044, p = 0.792) condition of the n-back task or error rate in the CPAL task (r = 0.133, p = 0.421).
Table 2 Association between Cognitive Testing Results and BDNF concentration. S BDNF
3.4. Cardiorespiratory fitness and BDNF concentration
DET OBK TBK CPAL
No correlation was demonstrated between VO2max and mean serum (r = 0.119, p = 0.469; Fig. 4A) or plasma (r=-0.129, p = 0.434; Fig. 4B) BDNF concentration.
P BDNF
M ± SEM
r
p
r
p
2.43 ± .01 1.26 ± .01 1.28 ± .02 15.01 ± 1.92
0.050 −0.046 0.215 0.108
0.761 0.784 0.194 0.514
−0.157 0.100 0.198 −0.257
0.341 0.551 0.234 0.115
4. Discussion 3.5. Cognitive performance and BDNF concentrations
4.1. Cardiorespiratory fitness and cognitive performance
No correlation was demonstrated between plasma or serum BDNF concentration and reaction time, OBK accuracy, TBK accuracy or CPAL error rate (p > 0.05, Table 2).
In the present study participants with high VO2max scores demonstrated significantly faster reaction times than their low fit counterparts. Additionally, higher cardiorespiratory fitness was positively associated with reaction time. These results replicate cross-sectional studies in older adult cohorts which demonstrate that fit individuals
Fig. 4. Association between VO2 max and BDNF concentration. There was no association between VO2max (ml.kg-1.min-1) and serum (A) or plasma (B) BDNF concentrations (p > 0.05), n = 39; Pearson correlation. 129
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quantification of cardiorespiratory fitness using a validated protocol in combination with indirect calorimetry No correlation was demonstrated between serum and plasma BDNF concentration and cardiorespiratory fitness. These results are similar to a number of studies which failed to identify an association between these variables [10,30,34,56,59,61]. However they are in contrast to previous studies which observed a positive relationship [23,64] and others that have demonstrated a negative association [1,7,14,31,32,44,48]. To date the studies which have demonstrated a positive association have included inactive older adults [64] or clinical populations [23,55]. In these cohorts small increases in cardiorespiratory fitness may lead to increases in circulating BDNF concentrations; however in young, fit populations it is possible that these small increases are not sufficient to cause a change. One plausible explanation underlying the present results is the homogenous cardiorespiratory fitness displayed by the participants. Participants were divided into a high or low VO2max group. Participants in the high VO2max group were correctly categorised as high fit, with mean VO2max values above the 90th percentile [45]. However, in the low fit group mean VO2max values corresponded to the 50th percentile, indicating that these participants might be more correctly classified as moderately fit, rather than low-fit. It is therefore possible that the association between cardiorespiratory fitness and BDNF was attenuated, as the present sample provides little information regarding the contrasting spectrums of aerobic capacity due to the relatively small differences in fitness levels between groups. In addition to its neurotrophic actions increasing evidence suggests a regulatory role for BDNF in body weight maintenance and energy homeostasis. BDNF correlates positively with BMI [40,42]. Furthermore BDNF expression is elevated in response to metabolic conditions such as diabetes [54]. This upregulation of BDNF likely represents a compensatory response to ameliorate the deleterious effects of abnormal glucose regulation on metabolism [43]. Participants presented with healthy body composition and therefore BDNF upregulation as a metabolic compensatory mechanism was unlikely to be present in this population. Additionally, all participants were well educated (17.23 ± 0.31 years) and close to the age when executive function is thought to be highest [63]. It is possible that the young cognitively intact brain has less need for BDNF regulated mechanisms to improve function compared to clinical or elderly populations who are at risk of cognitive decline. Taken together it is possible that in healthy adults less BDNF is needed for the maintenance of both metabolic and cognitive behaviours and this may underlie the lack of association presented in this study.
consistently outperform their low fit counterparts on reaction and movement times [9,53]; thus providing evidence that the positive assocation between and pyschomotor speed is apparent across a range of age groups. In contrast, no difference in cognitive performance was demonstrated between high and low fit participants and no correlation was observed between cardiorespiratory fitness and cognitive performance in the OBK, TBK or CPAL tasks. These tasks measure working memory, and visual learning and memory respectively which are components of executive control. These results contrast findings in a meta-analysis of older adults which demonstrated a positive association between executive control and cardiorespiratory fitness [11]. While decrements in cognitive function have been demonstrated in the third and fourth decade of healthy, educated adults [47], age-related cognitive decline is typically not apparent until after the sixth decade [49]. Decreased cognitive performance may already be apparent in older adults and therefore smaller increments in cardiorespiratory fitness may have a larger beneficial effect on executive control. In younger cohorts, in the absence of cognitive or structural impairment it is possible that small increases in cardiorespiratory fitness are not sufficient to lead to cognitive change. Relative to the aging literature comparatively fewer studies have examined the relationship between cardiorespiratory fitness and cognitive function in young adults. Existing research in these cohorts vary greatly in sample size, neuropsychological measure and fitness assessment utilized which limits definitive conclusions being drawn. While positive effects have been observed [2,31,38,51] others have failed to find any association [27,50] or have observed a relationship on some measures only [38]. While positive findings were demonstrated for reaction time in the present study, we failed to observe an association between cardiorespiratory fitness and performance on the n-back task. Our findings are inconsistent with recent research which examined the association between working memory and cardiorespiratory fitness in college-aged individuals [31,51]. Larger sample sizes and a greater diversity of fitness levels may have contributed to our equivocal findings and highlight the importance of including a spectrum of cardiorespiratory fitness levels in future research. A further potential explanation for these observations is that the cognitive measures utilised may not have been sensitive enough to detect change. In younger cohorts increased efficiency of brain functioning as a result of higher cardiorespiratory fitness has been demonstrated without associated improvements in behavioural performance [33,57]. This suggests that the effects of cardiorespiratory fitness on behavioral measures of cognitive performance may only emerge in high-functioning groups when the task is extremely difficult [58]. Increasing the task difficulty in younger cohorts may reduce the chances of ceiling effect in future studies. Furthermore, neuroimaging techniques may allow detection of exercise induced change at the cortical level that is not readily observable at the behavioral level.
4.3. BDNF and cognitive performance No correlations were demonstrated between cognitive task performance and BDNF concentration. To date the strongest evidence to support the putative role of BDNF in cognitive performance has been obtained using animal models. Animals administered exogenous neural injections of BDNF demonstrate improvements in spatial learning and memory [8] and object recognition learning [25]. Conversely in animals where the endogenous expression of hippocampal BDNF is blocked declines in cognitive performance are noted [41]. Collectively these studies demonstrate the importance of BDNF for cognitive performance in animal models. To date very limited literature exists relating BDNF to cognition in humans. Positive links between peripheral BDNF concentration and cognitive performance have been demonstrated [16,55].Furthermore associations have been shown between BDNF concentrations and severity of cognitive decline in Alzheimer’s disease. [36]. Collectively this literature provides preliminary support for the importance of BDNF for cognitive performance and brain health; however, these findings were not replicated in the current study. More research is needed to further elucidate the link between these factors.
4.2. BDNF and cardiorespiratory fitness Mean serum and plasma BDNF concentration were similar in participants classified as having a high versus low level of cardiorespiratory fitness. These results are similar to previous findings which have demonstrated no significant difference in circulating BDNF concentration between active and inactive participants [43,59,62]. However they are in contrast to results from studies that have demonstrated higher [4,13,65] and lower [1,6,43] BDNF concentrations in high fit participants. A possible explanation for this discrepancy is that existing literature is limited by the use of subjective measures to quantify fitness. These methods are open to reporting bias and may inadvertently reflect the influence of other variables on cognition such as a healthy lifestyle. Objective measurement has previously been highlighted as necessary to advance research into the area of physical activity and BDNF [43]. A strength of the present investigation was the 130
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[11] S. Colcombe, A.F. Kramer, Fitness effects on the cognitive function of older adults: a meta-analytic study, Psychol. Sci. 14 (2003) 125–130. [12] A. Collie, P. Maruff, D.G. Darby, M. McStephen, The effects of practice on the cognitive test performance of neurologically normal individuals assessed at brief test-retest intervals, J. Int. Neuropsychol. Soc. 9 (2003) 419–428. [13] P.R. Correia, F.A. Scorza, S. Gomes da Silva, A. Pansani, M. Toscano-Silva, A.C. de Almeida, R.M. Arida, Increased basal plasma brain-derived neurotrophic factor levels in sprint runners, Neurosci. Bull. 27 (2011) 325–329. [14] J. Currie, R. Ramsbottom, H. Ludlow, A. Nevill, M. Gilder, Cardio-respiratory fitness, habitual physical activity and serum brain derived neurotrophic factor (BDNF) in men and women, Neurosci. Lett. 451 (2009) 152–155. [15] L.A. Cysique, P. Maruff, D. Darby, B.J. Brew, The assessment of cognitive function in advanced HIV-1 infection and AIDS dementia complex using a new computerised cognitive test battery, Arch. Clin. Neuropsychol. 21 (2006) 185–194. [16] K.I. Erickson, R.S. Prakash, M.W. Voss, L. Chaddock, S. Heo, M. McLaren, B.D. Pence, S.A. Martin, V.J. Vieira, J.A. Woods, E. McAuley, A.F. Kramer, Brainderived neurotrophic factor is associated with age-related decline in hippocampal volume, J. Neurosci. 30 (2010) 5368–5375. [17] K.I. Erickson, R.S. Prakash, M.W. Voss, L. Chaddock, L. Hu, K.S. Morris, S.M. White, T.R. Wojcicki, E. McAuley, A.F. Kramer, Aerobic fitness is associated with hippocampal volume in elderly humans, Hippocampus 19 (2009) 1030–1039. [18] K.I. Erickson, M.W. Voss, R.S. Prakash, C. Basak, A. Szabo, L. Chaddock, J.S. Kim, S. Heo, H. Alves, S.M. White, T.R. Wojcicki, E. Mailey, V.J. Vieira, S.A. Martin, B.D. Pence, J.A. Woods, E. McAuley, A.F. Kramer, Exercise training increases size of hippocampus and improves memory, Proc. Natl. Acad. Sci. U. S. A. 108 (2011) 3017–3022. [19] J.L. Etnier, W. Salazar, D.M. Lander, S.J. Petruzzello, M. Han, P. Nowell, The influence of physical fitness and exercise upon cognitive funtioning: a meta-analysis, J. Sport Exerc. Psychol. 19 (1997) 249–277. [20] M.G. Falleti, P. Maruff, A. Collie, D.G. Darby, Practice effects associated with the repeated assessment of cognitive function using the CogState battery at 10-minute, one week and one month test-retest intervals, J. Clin. Exp. Neuropsychol. 28 (2006) 1095–1112. [21] G. Favalli, J. Li, P. Belmonte-de-Abreu, A.H. Wong, Z.J. Daskalakis, The role of BDNF in the pathophysiology and treatment of schizophrenia, J. Psychiatr. Res. 46 (2012) 1–11. [22] I. Ferrer, E. Goutan, C. Marin, M.J. Rey, T. Ribalta, Brain-derived neurotrophic factor in Huntington disease, Brain Res. 866 (2000) 257–261. [23] A. Fukushima, S. Kinugawa, T. Homma, Y. Masaki, T. Furihata, T. Yokota, S. Matsushima, T. Abe, T. Suga, S. Takada, T. Kadoguchi, R. Katsuyama, K. Oba, K. Okita, H. Tsutsui, Decreased serum brain-derived neurotrophic factor levels are correlated with exercise intolerance in patients with heart failure, Int. J. Cardiol. 168 (2013) e142–144. [24] F. Gomez-Pinilla, S. Vaynman, Z. Ying, Brain-derived neurotrophic factor functions as a metabotrophin to mediate the effects of exercise on cognition, Eur. J. Neurosci. 28 (2008) 2278–2287. [25] E.W. Griffin, R.G. Bechara, A.M. Birch, A.M. Kelly, Exercise enhances hippocampaldependent learning in the rat: evidence for a BDNF-related mechanism, Hippocampus 19 (2009) 973–980. [26] D. Hammers, E. Spurgeon, K. Ryan, C. Persad, N. Barbas, J. Heidebrink, D. Darby, B. Giordani, Validity of a brief computerized cognitive screening test in dementia, J. Geriatr. Psychiatry Neurol. 25 (2012) 89–99. [27] S.M. Hayes, D.E. Forman, M. Verfaellie, Cardiorespiratory fitness is associated with cognitive performance in older but not younger adults, J. Gerontol. Ser. B Psychol. Sci. Social Sci. 71 (2016) 474–482. [28] V.G. Heyward, Advanced Fitness Assessment and Exercise Prescription United States of America, (2014). [29] D.W. Howells, M.J. Porritt, J.Y. Wong, P.E. Batchelor, R. Kalnins, A.J. Hughes, G.A. Donnan, Reduced BDNF mRNA expression in the Parkinson’s disease substantia nigra, Exp. Neurol. 166 (2000) 127–135. [30] J. Hwang, R.M. Brothers, D.M. Castelli, E.M. Glowacki, Y.T. Chen, M.M. Salinas, J. Kim, Y. Jung, H.G. Calvert, Acute high-intensity exercise-induced cognitive enhancement and brain-derived neurotrophic factor in young, healthy adults, Neurosci. Lett. 630 (2016) 247–253. [31] J. Hwang, D.M. Castelli, F. Gonzalez-Lima, The positive cognitive impact of aerobic fitness is associated with peripheral inflammatory and brain-derived neurotrophic biomarkers in young adults, Physiol. Behav. 179 (2017) 75–89. [32] S.H. Jung, J. Kim, J.M. Davis, S.N. Blair, H.C. Cho, Association among basal serum BDNF, cardiorespiratory fitness and cardiovascular disease risk factors in untrained healthy Korean men, Eur. J. Appl. Physiol. 111 (2011) 303–311. [33] K. Kamijo, K.C. O’Leary, M.B. Pontifex, J.R. Themanson, C.H. Hillman, The relation of aerobic fitness to neuroelectric indices of cognitive and motor task preparation, Psychophysiology 47 (2010) 814–821. [34] H. Khalil, M.A. Alomari, O. Khabour, A. Al-Hieshan, J.A. Bajwa, The association between physical activity with cognitive function and brain-derived neurotrophic factor in people with Parkinson’s disease: a pilot study, J. Aging Phys. Act. 25 (2017) 646–652. [35] P. Komulainen, M. Pedersen, T. Hänninen, H. Bruunsgaard, T.A. Lakka, M. Kivipelto, M. Hassinen, T.H. Rauramaa, B.K. Pedersen, R. Rauramaa, BDNF is a novel marker of cognitive function in ageing women: the DR’s EXTRA study, Neurobiol. Learn. Mem. 90 (2008) 596–603. [36] C. Laske, K. Stellos, N. Hoffmann, E. Stransky, G. Straten, G.W. Eschweiler, T. Leyhe, Higher BDNF serum levels predict slower cognitive decline in Alzheimer’s disease patients, Int. J. Neuropsychopharmacol. 14 (2011) 399–404. [37] C. Laske, E. Stransky, T. Leyhe, G.W. Eschweiler, A. Wittorf, E. Richartz, M. Bartels, G. Buchkremer, K. Schott, Stage-dependent BDNF serum concentrations in
Limitations of the present study include the small sample size and volunteer participant group which is subject to self-selection bias. The association between cardiorespiratory fitness and psychomotor speed does not imply any causal relationship. Moreover, any directionally of causation cannot be inferred. While cardiorespiratory fitness may improve or preserve psychomotor speed, superior cognitive function may lead individuals to partake in increased levels of aerobic training. Preexisting activity levels were not controlled and as a result a limited spectrum of aerobic capacity is included. To accommodate for this limitation future projects should aim to study a population with diverse levels of cardiorespiratory fitness in order to elucidate the relationship between BDNF, cardiorespiratory fitness and cognition. It is more likely that large differences in physical fitness will reveal a difference in cognitive aptitude. 5. Conclusion In conclusion the present study demonstrates a significant negative correlation between VO2max and reaction time. Mean BDNF concentration was not significantly different between participants with high or low VO2max scores and did not correlate with cardiorespiratory fitness. Furthermore, no correlation was demonstrated between BDNF and cognitive performance. Future studies examining this relationship in diverse populations including older adults and clinical populations at risk of cognitive decline are needed in order to yield further insight into the interactive relationship between BDNF, cognitive function and cardiorespiratory fitness. Funding This research did not receive any specific grant from funding agencies in the public, commercial or not for profit sector. Ethical approval The experimental protocol was approved by the Ethics Committee for Research Involving Human Participants, Faculty of Health Sciences, Trinity College Dublin (Ethics Ref 201009). References [1] P. Babaei, A. Damirchi, M. Mehdipoor, B.S. Tehrani, Long term habitual exercise is associated with lower resting level of serum BDNF, Neurosci. Lett. 566 (2014) 304–308. [2] C.L. Baym, N.A. Khan, A. Pence, L.B. Raine, C.H. Hillman, N.J. Cohen, Aerobic fitness predicts relational memory but not item memory performance in healthy young adults, J. Cogn. Neurosci. 26 (2014) 2645–2652. [3] R.G. Bechara, A.M. Kelly, Exercise improves object recognition memory and induces BDNF expression and cell proliferation in cognitively enriched rats, Behav. Brain Res. 245 (2013) 96–100. [4] M. Belviranli, N. Okudan, B. Kabak, M. Erdogan, M. Karanfilci, The relationship between brain-derived neurotrophic factor, irisin and cognitive skills of endurance athletes, Phys. Sportsmed. 44 (2016) 290–296. [5] R.A. Bruce, J.R. Blackmon, J.W. Jones, G. Strait, Exercising testing in adult normal subjects and cardiac patients, Pediatrics 32 (Suppl) (1963) 742–756. [6] K.L. Chan, K.Y. Tong, S.P. Yip, Relationship of serum brain-derived neurotrophic factor (BDNF) and health-related lifestyle in healthy human subjects, Neurosci. Lett. 447 (2008) 124–128. [7] H.C. Cho, J. Kim, S. Kim, Y.H. Son, N. Lee, S.H. Jung, The concentrations of serum, plasma and platelet BDNF are all increased by treadmill VO(2)max performance in healthy college men, Neurosci. Lett. 519 (2012) 78–83. [8] F. Cirulli, A. Berry, F. Chiarotti, E. Alleva, Intrahippocampal administration of BDNF in adult rats affects short-term behavioral plasticity in the Morris water maze and performance in the elevated plus-maze, Hippocampus 14 (2004) 802–807. [9] L. Clarkson-Smith, A.A. Hartley, Relationships between physical exercise and cognitive abilities in older adults, Psychol. Aging 4 (1989) 183–189. [10] F.Gd.M. Coelho, T.M. Vital, A.M. Stein, F.J. Arantes, A.V. Rueda, R. Camarini, E. Teodorov, R.F. Santos-Galduróz, Acute aerobic exercise increases brain-derived neurotrophic factor levels in elderly with Alzheimer’s disease, J. Alzheimer Dis. 39 (2014) 401–408.
131
Neuroscience Letters 704 (2019) 126–132
J.M. Fortune, et al.
Sports Exerc. 48 (2016) 1994–2002. [52] P.J. Smith, J.A. Blumenthal, B.M. Hoffman, H. Cooper, T.A. Strauman, K. WelshBohmer, J.N. Browndyke, A. Sherwood, Aerobic exercise and neurocognitive performance: a meta-analytic review of randomized controlled trials, Psychosom. Med. 72 (2010) 239–252. [53] W.W. Spirduso, Reaction and movement time as a function of age and physical activity level, J. Gerontol. 30 (1975) 435–440. [54] M. Suwa, H. Kishimoto, Y. Nofuji, H. Nakano, H. Sasaki, Z. Radak, S. Kumagai, Serum brain-derived neurotrophic factor level is increased and associated with obesity in newly diagnosed female patients with type 2 diabetes mellitus, Metabolism 55 (2006) 852–857. [55] W. Swardfager, N. Herrmann, S. Marzolini, M. Saleem, P. Shammi, P.I. Oh, P.R. Albert, M. Daigle, A. Kiss, K.L. Lanctot, Brain derived neurotrophic factor, cardiopulmonary fitness and cognition in patients with coronary artery disease, Brain Behav. Immun. 25 (2011) 1264–1271. [56] D.L. Swift, N.M. Johannsen, V.H. Myers, C.P. Earnest, J.A.J. Smits, S.N. Blair, T.S. Church, The effect of exercise training modality on serum brain derived neurotrophic factor levels in individuals with type 2 diabetes, PLoS One 7 (2012). [57] J.R. Themanson, C.H. Hillman, Cardiorespiratory fitness and acute aerobic exercise effects on neuroelectric and behavioral measures of action monitoring, Neuroscience 141 (2006) 757–767. [58] M.W. Voss, L.S. Nagamatsu, T. Liu-Ambrose, A.F. Kramer, Exercise, brain, and cognition across the life span, J. Appl. Physiol. 111 (2011) 1505–1513. [59] A. Waschbisch, I. Wenny, A. Tallner, S. Schwab, K. Pfeifer, M. Maurer, Physical activity in multiple sclerosis: a comparative study of vitamin D, brain-derived neurotrophic factor and regulatory T cell populations, Eur. Neurol. 68 (2012) 122–128. [60] A.M. Weinstein, M.W. Voss, R.S. Prakash, L. Chaddock, A. Szabo, S.M. White, T.R. Wojcicki, E. Mailey, E. McAuley, A.F. Kramer, K.I. Erickson, The association between aerobic fitness and executive function is mediated by prefrontal cortex volume, Brain Behav. Immun. 26 (2012) 811–819. [61] A.S. Whiteman, D.E. Young, X. He, T.C. Chen, R.C. Wagenaar, C.E. Stern, K. Schon, Interaction between serum BDNF and aerobic fitness predicts recognition memory in healthy young adults, Behav. Brain Res. 259 (2014) 302–312. [62] R. Winker, I. Lukas, T. Perkmann, H. Haslacher, E. Ponocny, J. Lehrner, D. Tscholakoff, P. Dal-Bianco, Cognitive function in elderly marathon runners: cross-sectional data from the marathon trial (APSOEM), Wien. Klin. Wochenschr. 122 (2010) 704–716. [63] P.D. Zelazo, F.I. Craik, L. Booth, Executive function across the life span, Acta Psychol. 115 (2004) 167–183. [64] A. Zembron-Lacny, W. Dziubek, M. Rynkiewicz, B. Morawin, M. Wozniewski, Peripheral brain-derived neurotrophic factor is related to cardiovascular risk factors in active and inactive elderly men, Braz. J. Med. Biol. Res. 49 (2016). [65] J.A. Zoladz, A. Pilc, J. Majerczak, M. Grandys, J. Zapart-Bukowska, K. Duda, Endurance training increases plasma brain-derived neurotrophic factor concentration in young healthy men, J. Physiol. Pharmacol. 59 (Suppl 7) (2008) 119–132.
Alzheimer’s disease, J. Neural Transm. 113 (2006) 1217–1224. [38] P.D. Loprinzi, C.J. Kane, Exercise and cognitive function: a randomized controlled trial examining acute exercise and free-living physical activity and sedentary effects, Mayo Clin. Proc. 90 (2015) 450–460. [39] P. Maruff, E. Thomas, L. Cysique, B. Brew, A. Collie, P. Snyder, R.H. Pietrzak, Validity of the CogState brief battery: relationship to standardized tests and sensitivity to cognitive impairment in mild traumatic brain injury, schizophrenia, and AIDS dementia complex, Arch. Clin. Neuropsychol. 24 (2009) 165–178. [40] P. Monteleone, M. Fabrazzo, V. Martiadis, C. Serritella, M. Pannuto, M. Maj, Circulating brain-derived neurotrophic factor is decreased in women with anorexia and bulimia nervosa but not in women with binge-eating disorder: relationships to co-morbid depression, psychopathology and hormonal variables, Psychol. Med. 35 (2005) 897–905. [41] J.S. Mu, W.P. Li, Z.B. Yao, X.F. Zhou, Deprivation of endogenous brain-derived neurotrophic factor results in impairment of spatial learning and memory in adult rats, Brain Res. 835 (1999) 259–265. [42] M. Nakazato, K. Hashimoto, E. Shimizu, C. Kumakiri, H. Koizumi, N. Okamura, M. Mitsumori, N. Komatsu, M. Iyo, Decreased levels of serum brain-derived neurotrophic factor in female patients with eating disorders, Biol. Psychiatry 54 (2003) 485–490. [43] Y. Nofuji, M. Suwa, Y. Moriyama, H. Nakano, A. Ichimiya, R. Nishichi, H. Sasaki, Z. Radak, S. Kumagai, Decreased serum brain-derived neurotrophic factor in trained men, Neurosci. Lett. 437 (2008) 29–32. [44] N.H. Pedersen, J. Tarp, L.B. Andersen, A.K. Gejl, T. Huang, L. Peijs, A. Bugge, The association between serum brain-derived neurotrophic factor and a cluster of cardiovascular risk factors in adolescents: the CHAMPS-study DK, PLoS One 12 (2017) e0186384. [45] S.L. Pescatello, ACSM’s Guidelines for Exercise Testing and Prescription, Wolters Kluwer/Lippincott Williams & Wilkins Health, Philadelphia, USA, 2014. [46] R.H. Pietrzak, J. Olver, T. Norman, D. Piskulic, P. Maruff, P.J. Snyder, A comparison of the CogState schizophrenia battery and the measurement and treatment research to improve cognition in schizophrenia (MATRICS) battery in assessing cognitive impairment in chronic schizophrenia, J. Clin. Exp. Neuropsychol. 31 (2009) 848–859. [47] T.A. Salthouse, When does age-related cognitive decline begin? Neurobiol. Aging 30 (2009) 507–514. [48] P. Scalzo, A. Kummer, T.L. Bretas, F. Cardoso, A.L. Teixeira, Serum levels of brainderived neurotrophic factor correlate with motor impairment in Parkinson’s disease, J. Neurol. 257 (2010) 540–545. [49] K.W. Schaie, S.L. Willis, G.I. Caskie, The Seattle longitudinal study: relationship between personality and cognition, Neuropsychol. Dev. Cogn. B Aging Neuropsychol. Cogn. 11 (2004) 304–324. [50] J.L. Scisco, P.A. Leynes, J. Kang, Cardiovascular fitness and executive control during task-switching: an ERP study, Int. J. Psychophysiol. 69 (2008) 52–60. [51] S.P. Scott, D.E.S. MJ, K. Koehler, D.L. Petkus, L.E. Murray-Kolb, Cardiorespiratory fitness is associated with better executive function in young women, Med. Sci.
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