Publisher: Taylor & Francis

Journal: Expert Review of Neurotherapeutics

DOI: 10.1080/14737175.2016.1179582

Review

Exercise-induced neuroprotective effects on neurodegenerative diseases: the key role of trophic factors

Carlos Campos1,2, Nuno Barbosa F. Rocha2, Eduardo Lattari1, Flávia Paes1, António E. Nardi1, Sérgio Machado1,3

1Laboratory of Panic and Respiration, Institute of Psychiatry of Federal University of Rio de Janeiro (IPUB/UFRJ), Rio de Janeiro, Brazil 2Polytechnic Institute of Porto, School of Allied Health Sciences, Porto, Portugal 3Physical Activity Neuroscience Laboratory, Physical Activity Sciences Postgraduate Program - Salgado de Oliveira University (UNIVERSO), Niterói, Brazil

Corresponding Author: Carlos Campos, BSc. Laboratory of Panic and Respiration, Institute of Psychiatry of Federal University of Rio de Janeiro, Rio de Janeiro, Brazil; School of Health Technologies, Polytechnic Institute of Porto, Porto, Portugal;

Abstract

Age-related neurodegenerative disorders, like Alzheimer’s or Parkinson’s disease, are becoming a major issue to public health care. Currently, there is no effective pharmacological treatment to address cognitive impairment in these patients. Here, we aim to explore the role of exercise-induced trophic factor enhancement in the prevention or delay of cognitive decline in patients with

neurodegenerative diseases. There is a significant amount of evidence from animal and human studies that links neurodegenerative related cognitive deficits with changes on brain and peripheral trophic factor levels. Several trials with elderly individuals and patients with neurodegenerative diseases report exercise induced cognitive improvements and changes on trophic factor levels including BDNF, IGF-I, among others. Further studies with healthy aging and clinical populations are needed to understand how diverse exercise interventions produce different variations in trophic factor signaling. Genetic profiles and potential confounders regarding trophic factors should also be addressed in future trials.

Key-words: Exercise, Neuroprotective, Neurodegenerative Disease, Alzheimer’s Disease, Parkinson’s Disease, Neurotrophins, BDNF, IGF-I, NGF, GDNF

1. Introduction

Elderly population is rapidly increasing all around the world. In 2010 there were a total of

524 million people aged 65 or older and by 2050 this number is estimated to triple to 1.5 billion [1]. As life expectancy also increases, age-related neurodegenerative disorders, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), are becoming more prevalent and represent a major issue to health care systems [2, 3]. Neurodegenerative diseases are characterized by progressive structural and/or functional changes in the brain, leading to several degrees of cognitive impairment [4-6]. In the past few decades researchers have accomplished to further understand age-related neurodegenerative disorders, but there is still no effective pharmacological treatment to address the needs of these patients. Recently, physical exercise has been suggested as an effective, low-cost and low-risk alternative to tackle this public health priority.

It has been argued that exercise can be a preventing or disease-slowing therapeutic strategy for age-related neurodegenerative diseases, reducing its social and economic burden [7, 8]. Several meta-analysis provide clear evidence that physical exercise promotes cognitive function in numerous domains [9, 10] including in healthy older adults [11-14]. There is also a fair amount of evidence stating that physical exercise is associated with reduced incidence of dementia [15, 16], Mild Cognitive Impairment [MCI; 17] and lower risk of developing PD [18, 19]. Furthermore, there are also a significant number of systematic reviews reporting positive

cognitive effects of exercise in AD and other kinds of dementia [20, 21], PD [22] and MCI patients [21, 23, 24], mainly in global cognition, executive function, attention and delayed recall.

Recent developments in neuroimaging techniques and genetics allowed researchers to explore the neuroprotective mechanisms that underlie exercise induced improvements in neurodegenerative diseases [25, 26]. In the past few decades, researchers developed several animal studies in order to further understand how these neurobiological mechanisms promote neuroplasticity and improve cognition. Some authors argue that the differences between rodents and humans brain [e.g. number of neurons, protein expression] do not allow the findings on neurodegeneration and cognition from animal models of neurodegenerative diseases to be relevant to human therapy [27, 28]. However, using animal studies to understand the effects of exercise on the brain has been well established. Vivar and colleagues describe voluntary running in animal models as a critical tool to study exercise induced neural changes as it seems to mimic several biological brain responses that occur in humans [29]. Using this method researchers understood how exercise can increase the rate of neurogenesis within the dentate gyrus of the hippocampus [30, 31], even in older animals [32].

In addition, the findings regarding enhanced neurogenesis have been associated with learning and memory improvements [33, 34]. Neuroplasticity mechanisms activated by exercise are clearly a complex process but animal research has consistently provided evidence of an exercise induced cascade of partially interdependent functional and structural changes in the brain, including increased dendritic spine density and angiogenesis, enhanced long-term potentiation as well as augmented expression of neurotransmitters and trophic factors [29, 35].

Nowadays it is safe to say that physical exercise is able to promote synaptogenesis and maintain brain volume in elderly subjects [35, 36]. Along with animal evidence, human studies suggest that exercise may attenuate progression of neurodegenerative processes and age-related loss of synapses [8]. The most emergent and popular hypothesis to explain the relationship between psychical activity, cognition and neuroplastic mechanisms has been enhanced trophic factor signaling [37, 38]. Trophic factors such as brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), glial cell line-derived neurotrophic factor (GDNF) and insulin-like growth factor (IGF) have been identified as possible mediators of the protective and therapeutic effects of exercise on brain function [39, 40].

Several cellular and molecular mechanisms encompassing neurotrophic factors are important to maintain neuronal function and promote synaptic plasticity. In recent years, neurotrophins and their receptors have been highlighted as important regulators of adult neurogenesis. BDNF and its main receptors (TrkB and p75NTR) have been suggested to play a

critical role in dendrite/spine morphogenesis, axonal initiation and progenitor proliferation/migration, mechanisms which support neurogenesis in the dentate gyrus of hippocampal formation [41]. Furthermore, BDNF has also been related to enhanced synaptic plasticity [42-44], late phase long-term potentiation [45], neuronal survival and differentiation [46, 47] and protection against neuronal death in the hippocampus [48, 49]. IGF is another trophicfactor described as a potent anabolic and mitogenic agents which activates several intracellular signaling cascades through Trk receptors, controlling cell proliferation, survival and differentiation [50]. NGF plays a role in TrkA-mediated neuroprotection and cell survival, although there is also evidence it’s involvement in apoptosis [51, 52]. Finally, GDNF also has a neuroprotective role as it activates complex interactions between several signaling cascades responsible for cell differentiation and proliferation as well as survival of dopaminergic and noradrenergic neurons in adult brain [53].

Thereby, it seems increasingly more likely that exercise induced upregulation of trophic factors can promote angiogenesis, neurogenesis and synaptogenesis, which can ultimately prevent age-related functional and structural neurodegeneration and the concomitant cognitive decline [25, 54, 55]. The purpose of this paper is to review the evidence regarding the role of exercise-induced trophic factor enhancement in preventing or delaying the cognitive decline of age-related neurodegenerative disease. Firstly, the authors will start by exploring the role of various trophic factors in aging and age-related neurodegenerative disorders. The authors will then review findings, which relate exercise, trophic factor signaling changes and cognitive improvements in elderly individual and patients with several neurodegenerative disorders. Finally, we provide several recommendations and directions by which we can further increase our knowledge regarding the exercise induced neuroprotection and trophic factor upregulation in patients with neurodegenerative diseases.

Trophic Factors Signaling, Aging and Neurodegenerative Diseases

Trophic factor signaling has been widely explored in aging and neurodegenativediseases. Espinet and colleagues argue that the precursor proteins of neurotrophins [pro-neurotrophins] are implicated in the development of neurodegenerative diseases, as they play a role in the mechanisms related to neuron apoptosis [56]. These authors state that aging induced oxidative stress may enhance the expression of pro-neurotrophin forms, exacerbating its neurodegenerative effects. However, as we further describe throughout this section, there is a

significant amount of evidence regarding reduced trophic signaling in patients with neurodegenerative diseases, with the involvement of several trophic factors including BDNF, NGF, GDNF and IGF-I, among others.

2.1 Brain Derived Neurotrophic Factor (BDNF)

BDNF is a neurotrophin widely expressed in the human brain and is crucial to regulate neuroprotective, neurogenesis and neuroplasticity mechanisms [57, 58]. Evidence from animal and human studies describe the relationship between aging, BDNF and cognitive impairment [59-61]. Furthermore, dysfunction in BDNF signaling is related to the pathophysiologic mechanisms of several age-related neurodegenerative diseases [62-64]. Plasma or serum BDNF levels decline with age and its decrease correlates with reduced hippocampal volume and poor cognitive performance [65-67]. Reduced brain and peripheral expression of BDNF has also been described in patients with MCI [68-70]. Moreover, Forlenza and colleagues described that reduced BDNF levels in the cerebral spinal fluid [CSF] are associated with progression from MCI to AD [71].

BDNF is the most widely researched trophic factor and in recent years there has been a growing number of studies exploring brain and peripheral BDNF expression in AD [72-74]. Post-mortem studies consistently found reduced BDNF mRNA or protein levels in the hippocampus of AD patients [75-77] among other brain regions [78-80]. Peng and colleagues found that the diminution of BDNF levels in AD was correlated with the degree of cognitive impairment [69]. The authors suggest that BDNF can be a biological marker of preclinical AD and play an important role in the progressive neuronal loss across the course of the disease.

The main neurotrophin receptors, Trk receptors and p75NTR, have also been associated with the course of AD. Several cell survival and synaptic plasticity mechanisms are mediated by the interaction between neurotrophins and Trk receptors [81, 82]. Inversely, the interaction between neurotrophins and their precursors with p75NTR normally activates apoptotic pathways in peripheral neurons and glia [83, 84]. Some authors argue that the disparity between neuronal death and survival in AD may be caused by the upregulation of p75NTR and down regulation of TrK observed in these patients [85]. Furthermore, several authors reported consistently reduced NGF TrkA receptors in the basal forebrain and cortex of AD patients [86-88], which provides further evidence of impaired BDNF signaling in AD.

Regarding peripheral blood BDNF levels, findings have been somewhat inconsistent. While most studies state that serum/plasma BDNF concentration declines in AD patients [89-92], some have found increased levels [93] or no significant changes [73]. However, several

researches argue that BDNF levels can fluctuate accordingly to the stage or severity of the disease, with increase levels in early AD reflecting a compensatory neuroprotective mechanism to neuron distress [72, 94].

BDNF also seems to be evolved in PD since it has a crucial role in neurotoxin induced degeneration of dopaminergic neurons, which display an intense decline in these patients [62]. Reduced BDNF mRNA and protein expression have been consistently described in the substancia nigra of PD patients, which is the mainly affected neuronal group in PD [62, 95, 96]. Moreover, serum BDNF levels have been associated with disease progression and motor symptoms severity [97]. BDNF may also play a role in multiple sclerosis (MS) but findings are somewhat inconsistent, as some authors report decreased peripheral basal levels [98], while others describe no significant changes [99]. Interestingly, increased brain and CSF levels of BDNF have also been described in MS patients [100-102]. It seems that age-related neurodegenerative diseases are associated with reduced BDNF function, although BDNF levels may vary across specific brain regions and according to symptom severity.

2.2 Nerve Growth Factor (NGF)

NGF is one of the oldest described neurotrophins and is responsible for protecting neurons from chemical stressors as well as for neuronal growth and proliferation [103]. Findings from animal studies suggest that NGF decreases with aging, hindering the conservation of cholinergic neurons and playing a role on age-dependent decline in cognitive function [104, 105]. The role of NGF in age-related neurodegenerative diseases has also been explored, which allowed to determine that NGF levels were augmented in the dentate gyrus [80], although another study found no brain changes in NGF expression [106]. Several authors also found no significant differences between peripheral NGF levels in comparison to the control group [106, 107], although significant increases were found in CSF levels [108]. In contrast, numerous studies have described increased levels of pro-NGF in AD patients [109]. Regardless of inconsistent results, a recent study by Ferreira and colleagues found cognitive improvements and reduced levels of amyloid β after NGF treatment, which can suggest that this hormone may be an important target in AD [110].

2.3 Glial Cell Line-derived Neurotrophic Factor (GDNF)

GDNF has a significant role in the development and maintenance of spinal motor neurons and midbrain dopaminergic neurons [103, 111]. The neuroprotective effects of GDNF were explored by Pertusa and colleagues, who highlighted its role to attenuate the neuronal atrophy which underlies age-related cognitive deficits [112] . However, GDNF has a role in several neuron systems, which can explain why other authors found an increased age-related GDNF expression in the frontal cortex but not on the hippocampus [113]. Several authors have also reported reduced GDNF levels in AD and MCI patients [114, 115] in spite of others describing increased levels [116] or no differences in comparison to controls [107]. Interestingly, Straten and colleagues also found increased CSF levels of GDNF in early stage AD patients in contrast to reduced serum concentration, suggesting an adaptive response of the impaired brain [117]. As highlighted before, GDNF specifically protects the dopaminergic neurons through several mechanisms and its down regulation has been implicated in PD onset mechanisms [111]. Two cross sectional studies have found reduced levels of GDNF in patients with PD. Lower concentration of GDNF were found in the cerebellum and the frontal cortex of PD patients, although no significant changes were described in other brain regions, including the substancia nigra [118]. Conversely, Chauhan and colleagues reported reduced GDNF levels in the substancia nigra of PD patients, without any other trophic factor being affected [119]. Moreover, GDNF has been the main actor in several human trials, showing promising results as a potential therapeutic agent to treat PD through its neuroprotective and neurorestorative effects [120-122].

2.4 Insuline-like Growht Factor (IGF)

IGF has also been highlighted as a crucial hormone to brain cell proliferation, survival and neurogenesis [123]. IGF-I levels have been associated to cognitive decline [124] and its level also decreases progressively as we get older [125]. Aging is associated in reduction in both serum IGF-I and brain density of IGF-I receptors in the hippocampus [126]. Moreover, higher levels of IGF-I have been associated with larger brain volumes, which points out that this factor can be crucial to prevent neurodegeneration [127]. Regarding AD patients, brain measures found reduced expression of IGF mRNA, with levels decreasing at more advanced stages of the disease [128]. Others authors state that IGF-I inhibition slows the progression to AD [129]. Changes in CSF and blood plasma levels of IGF-II have also been reported in patients with AD [130] and lower serum levels of IGF-I were also associated with a superior risk to develop AD [127].

The previously described trophic factors are those mainly researched when addressing age-related neurodegenerative diseases. Other factors such as stem cell factor (SCF), granulocyte-colony stimulating factor (G-CSF), and vascular endothelial growth factor (VEGF), among others have also been explored [103]. All the evidence clearly suggests that trophic signaling plays a key role in aging and neurodegenerative diseases. Establishing trophic factors as potential targets to prevent neurodegeneration and promote neuroprotection can be a critical step in order to improve treatments for age-related neurodegenerative diseases.

3. Exercise, Trophic Factors Signaling and Cognition

In the past few years, trophic factors have been explored as the possible mediators ofexercise induced brain plasticity. Evidence from animal and human studies show that exercise enhances expression of several trophic factors such as BDNF, IGF-I, NGF, among others, both in health elderly individuals (Table 1) as well as in patients with neurodegenerative disease [Table 2; 54, 131-134].

Researchers have highlighted BDNF as the neurotrophin which is more susceptible to exercise induced changes. A recent meta-analysis by Szuhany et al. [2015] reported that both acute and regular exercise can increase BDNF levels in healthy subjects and clinical populations [135]. Several studies with healthy humans reported that physical exercise can increase plasma and/or serum BDNF concentration, either after acute exercise or chronic aerobic exercise [136,

Furthermore, the review by Coelho and colleagues highlighted that both acute or chronic physical exercise increases peripheral BDNF concentrations in healthy elderly individuals, emphasizing the role of aerobic training as well as strength exercise programs [138]. There are also several studies with healthy elderly subjects or with participants with non-degenerative diagnosis [e.g. frailty, depressive symptoms] that report exercise induced BDNF upregulation [139-142], although two of these studies did not had any male participants. Other authors explored the effects of aerobic exercise on older adults and found no significant changes in peripheral BDNF levels after the intervention [131, 143]. However, Erickson and colleagues reported a crucial finding regarding BDNF induced neuroplastic changes, as participants with larger BDNF changes after exercise displayed higher hippocampal volume enlargement [144].

Several studies with MCI patients found increased peripheral BDNF levels after a psychical exercise intervention [145, 146]. Interestingly, Baker and colleagues described an enhancement of BDNF and IGF-I plasma levels in MCI patients after a 6 month aerobic exercise

program, but only male participants displayed these changes [147]. Female participants actually displayed reduced BDNF levels after the intervention. In AD patients, Coelho and colleagues also found a significant correlation between plasma BDNF levels and the level of physical exercise practiced by participants [89].

There are also two studies reporting exercise induced peripheral BDNF levels enhancement in patients with PD. Zoladz and colleagues reported increases in serum BDNF levels after a single bout of aerobic bicycle training in PD patients [148]. A follow-up study by Marusiak and colleagues found increases in BDNF levels after interval exercise, which were correlated with improvement in motor symptoms [149]. However, both these studies did not report information regarding baseline group differences and did not use a control group with PD patients, which would be important to validate these findings.

Regarding MS, there is evidence of exercise induced enhancement in BDNF levels after an acute exercise session [99] or following prolonged training programs [98, 150]. Schulz and colleagues reported no significant changes in BDNF after an aerobic exercise intervention, but the participants only completed sessions twice a week, a reduced frequency in comparison to previously mentioned studies [151].

There is also evidence linking BNDF enhancement to cognitive performance in elderly individuals. Anderson-Hanley and colleagues found a reduced rate of conversion to MCI after a cyber cycling exergame intervention, with participants also displaying a significant increase in BDNF levels which may have led to the reported cognitive effects [141]. Suzuki and colleagues also reported that elevated BDNF levels could predict cognitive improvement in older adults with MCI after an exercise intervention [152].

Exercise induced neuroprotection in the adult brain has also been related to modulation of IGF-I levels. Animal studies suggests that exercise promotes IGF-I uptake and neurogenesis by specific groups of neurons throughout the brain [153, 154]. Thereby, Carro and colleagues suggest that circulating IGF-I can be increased by exercise, providing a key factor to prevent or delay age and disease-related cognitive decline [155]. However, there is a clear need to further extend research in humans since results are inconsistent. Cassilhas and colleagues reported that resistance training increased peripheral IGF-I levels in healthy older adults [156] and Baker reporting exercise induced elevation of plasma IGF-I levels in men with MCI [147]. No significant differences were found in resting IGF-I concentration after training in MS patients [98] and some authors even report that aerobic exercise can lower IGF-I serum levels in healthy young and elderly subjects [131, 157].

Although BDNF and IGF-I have been further explored, researchers have also paid attention to other trophic factors. The neuroprotective role of NGF in aging and neurodegenerative diseases has also been explored, mainly in animal studies which found exercise induced NGF up regulation in aging rats and AD models [158, 159], although findings in human studies remain fairly inconsistent. Coelho and colleagues found no changes either in NGF and GDNF levels after a resistance training intervention in elderly women. NGF has also been further explored in MS patients, with findings suggesting that acute and maintained exercise may allow for peripheral NGF improvements [99, 150]. However, Schulz and colleagues actually found a trend to reduced NGF acute response after a personalized aerobic training program [151]. Animal studies have also reported increased VEGF peripheral levels after aerobic exercise, suggesting its involvement in exercise-induced neurogenesis and synaptic plasticity [160]. Baseline VEGF levels in older subjects are also correlated with enhanced exercise induced improvements in temporal cortex connectivity, which further strengthens the role of VEGF in the brain effects achieved by exercise [131].

Finally, it is also important to emphasize that the cellular source of exercise-induced trophic signaling changes is only partially understood. It has been argued that neurotrophic factors do not readily cross the blood-brain barrier (BBB), which has hindered their use as a therapeutic target for neurodegenerative diseases [161]. However, there is also evidence describing that exercise increases BBB permeability [162, 163] and that neurotrophins can cross it [164], which increases the likelihood of peripheral neurotrophins to cross the BBB after exercise in order to support neural health. For instance, BDNF can cross the BBB bi-directionally which allows to postulate several possible relationships between brain and plasma neurotrophic levels [165]. It is reasonable to assume that exercise induced blood flow to the brain enhances central neurotrophins expression [166, 167], as there is evidence of BDNF release in the brain during exercise [168]. After being produced, these neurotrophins may leave the brain in order to be stored in other body regions. It is also possible that increased peripheral neurotrophin levels induced by exercise are gradually cleared after exercise [169]. It is assumed that regardless of exercise intensity, peripheral BDNF concentration returns back to baseline within 15-60 minutes, decreasing to sub-baseline levels after that period [170], which can indicate that these molecules are used in the periphery or transported to the brain in order to promote neural health.

Furthermore, we also have to account that different trophic factors are produced in difference areas. BDNF is mainly produced in the brain but it can also be produced by tissues in the periphery, mostly being released into circulation and stored in platelets [171] or produced by muscle cells where it is used locally [172]. On the other hand, while IGF-I is primarily produced by

the liver [173], when released in high concentrations it can cross de BBB barrier, triggering increased BDNF expression in the brain [37, 174]. Trophic factors are synthetized and released in numerous regions, which lead researchers to struggle when trying to pinpoint whether exercise induced peripheral neurotrophins increase is caused by changes in peripheral or central mechanisms [62, 175].

4. Expert commentary

In this article, we have reviewed the link between trophic factors and age-relatedneurodegenerative diseases and how they play a key role on exercise-induced neuroprotective effects for these patients. There is a significant amount of clinical trials that report the effectiveness of physical exercise as an alternative intervention to address age-related cognitive impairment. Support for acknowledging exercise as a valuable intervention to the treatment of age-related neurodegenerative diseases comes from studies linking exercise to cognitive improvements and trophic signaling enhancement, which highlights trophic factors as important therapeutic targets to stimulate neuroprotective mechanisms [58, 176, 177].

Several trophic factors have been implicated in the pathogenesis and pathophysiology of age-related neurodegenerative diseases, but BDNF is by far the most widely studied and proven neurotrophin regarding exercise induced neurobiological effects. There have been few clinical trials exploring the role of other trophic factors, although there are some authors reporting the involvement of IGF-I and even NGF. Furthermore, numerous questions remain to be answered regarding the cellular mechanisms of exercise induced trophic signaling. Regardless, as the evidence regarding exercise induced brain changes in neurodegenerative diseases gradually increases, it seems highly unlikely that peripheral neurotrophic factors do not play a direct role in the underlying neuroplastic mechanisms or are at least an important indicator of enhanced neuroplastic activity.

Finally, it is still hard to precisely define which exercise conditions (type, duration and intensity) are recommended to trigger neuroprotective effects, in spite of some reviews suggesting moderate intensity aerobic and resistance exercise [8, 132]. Knaepen and colleagues state that acute aerobic exercise is more likely to elevate BDNF concentration than acute strength exercise, in healthy subjects or in patients with chronic diseases [170]. Furthermore, most studies report a significant dose-response relationship between acute aerobic exercise intensity and BDNF concentration. However, there are several biases from the reported studies which hinder the clinician’s possibility to recommend the most effective exercise intervention, as several

studies have reduced samples sizes, lack an appropriate control group or do not report accurately on data regarding exercise intensity. Most studies found no significant differences between-groups regarding gender and age or accounted for potential discrepancies adding these variables as covariates, but some studies which do report significant intervention effects do not present any data regarding baseline differences (Table 1 and 2). Regardless of all these reservations, it is safe to think about exercise-induced neuroprotective effects with two main premises. First, each exercise session results in enhanced neurotrophic activity that becomes gradually larger as we engage more regularly in physical exercise [135]. Second, as we try to accurately determine the right dosage to induce brain changes, it may be reasonable follow the international exercise recommendations for the elderly, which advises 5 weekly 30 minutes sessions of moderate intensity aerobic exercise [178].

5. Five-year view

Further understanding about the role of trophic factors on exercise-induced cognitive

improvement and neuroprotective mechanisms can be attained by developing clinical trials with elderly or patients with age-related neurodegenerative diseases. Researchers must be highly methodical when developing these trials, using matched control patients groups and clearly defining the characteristics of the exercise intervention they want to explore.

However, regardless of which trophic factors account for neuroprotective mechanisms, researchers and clinicians must take into account several aspects that can influence the brains response to physical exercise. Future studies should make an effort to accurately pinpoint the exercise components that are responsible for cognitive outcomes and their neurobiological underpinnings. Neuroprotective and neuroplastic factors have a distinct role in this process, but there is a need to further understand the mechanisms which underlie these deficits. If animal studies report that specific training procedures induce different types of brains changes [40], we can only assume that the human brain will have distinct responses as well and there is a need to further understand and predict how does the human brain react to specific training procedures. Moreover, understanding proficiently exercise-induced neuroprotective mechanisms can also help to explore pharmacological alternatives that can recreate some of the effects achieved by exercise, allowing to develop alternative treatment strategies which target trophic factors [92, 179-183].

Trophic factor levels vary widely between individual and research teams should account for potential confounders (e.g. age, gender, race) when designing exercise protocols and

interpreting trial results [184]. Furthermore, methods to assess trophic factor signaling are far from being perfect and there is a need to develop new assessment techniques to keep track of brain levels of trophic factors. Genetic and/or environmental factors have a role on the response of the brain to physical activity and must be addressed to develop more individualized programs that are adapted to each patient’s aging and diagnosis [37].

It is clear that nowadays we are not able to perfectly describe the pathways between exercise, cognitive improvement and trophic factors. It is also clear that exercise has a crucial role on brain health during aging and neurodegenerative processes. This highlights the importance to develop clinical trials targeted to further understand how we can use exercise to prevent or treat cognitive decline associated with age-related neurodegenerative diseases, helping these patients to improve their daily functioning and their quality of life.

Most of the included studies have reduced samples sizes

6. Key-issues- In spite of extensive research regarding age-related neurodegenerative disorders

(Alzheimer’s disease Parkinson’s Diseases, among others), there is still no effective pharmacological treatments to address the needs of these patients.

- Exercise has been clearly proven as an effective and low-cost alternative to address age related cognitive decline or to slow cognitive impairment associated to age-related neurodegenerative diseases.

- Trophic factors such as BDNF, NGF, GDNF and IGF-I have been widely explored as important actors in the pathogenesis and pathophysiology of age-related neurodegenerative disorders.

- There is a growing amount of evidence supporting that neurotrophic factors play a direct role in the underlying neuroplastic mechanisms or are at least an important indicator of enhanced neuroplastic activity.

- Exercise has been postulated to enhance the expression of several trophic factors but BDNF is by far the most widely studied and proven neurotrophin regarding exercise induced neurobiological effects.

- There is a need to develop high quality randomized controlled trials in order to strengthen the evidence regarding exercise-induced cognitive improvement and neuroprotective mechanisms in the elderly or patients with age-related neurodegenerative diseases.

- Future work should also further explore the cellular mechanisms of exercise induced trophic signaling, in order to understand the role of central and peripheral mechanisms.

- Researchers should make effort to pinpoint which exercise components (e.g. type, duration, frequency) are responsible for cognitive outcomes and their neurobiological underpinnings in age-related neurodegenerative disorders.

Declaration of Interest The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

References

Papers of special note have been highlighted as: * of interest** of considerable interest

1. Department of Economic and Social Affairs, United Nations. World Population Prospects:The 2010 Revision. 2011. Report No.: Contract No.: ST/ESA/SER.A/313. 2. Marques-Aleixo I, Oliveira PJ, Moreira PI, Magalhaes J, Ascensao A. Physical exerciseas a possible strategy for brain protection: evidence from mitochondrial-mediated mechanisms. Prog Neurobiol. 2012;99(2):149-62. 3. Bonaconsa M, Colavito V, Pifferi F, Aujard F, Schenker E, Dix S, et al. Cell clocks andneuronal networks: neuron ticking and synchronization in aging and aging-related neurodegenerative disease. Curr Alzheimer Res. 2013;10(6):597-608. 4. Yau SY, Gil-Mohapel J, Christie BR, So KF. Physical exercise-induced adultneurogenesis: a good strategy to prevent cognitive decline in neurodegenerative diseases? Biomed Res Int. 2014;2014:403120. 5. Padurariu M, Ciobica A, Mavroudis I, Fotiou D, Baloyannis S. Hippocampal neuronal lossin the CA1 and CA3 areas of Alzheimer's disease patients. Psychiatr Danub. 2012;24(2):152-8. 6. Kramberger MG, Stukovnik V, Cus A, Repovs G, Tomse P, Meglic NP, et al. Parkinson'sdisease dementia: clinical correlates of brain spect perfusion and treatment. Psychiatr Danub. 2010;22(3):446-9.

7. Rolland Y, Abellan van Kan G, Vellas B. Healthy brain aging: role of exercise andphysical activity. Clin Geriatr Med. 2010;26(1):75-87. 8. Ahlskog JE, Geda YE, Graff-Radford NR, Petersen RC. Physical exercise as apreventive or disease-modifying treatment of dementia and brain aging. Mayo Clin Proc. 2011;86(9):876-84. 9. Smith PJ, Blumenthal JA, Hoffman BM, Cooper H, Strauman TA, Welsh-Bohmer K, et al.Aerobic exercise and neurocognitive performance: a meta-analytic review of randomized controlled trials. Psychosom Med. 2010;72(3):239-52. 10. Roig M, Nordbrandt S, Geertsen SS, Nielsen JB. The effects of cardiovascular exerciseon human memory: a review with meta-analysis. Neurosci Biobehav Rev. 2013;37(8):1645-66. 11. Angevaren M, Aufdemkampe G, Verhaar HJ, Aleman A, Vanhees L. Physical activity andenhanced fitness to improve cognitive function in older people without known cognitive impairment. Cochrane Database Syst Rev. 2008(2):CD005381. 12. Kelly ME, Loughrey D, Lawlor BA, Robertson IH, Walsh C, Brennan S. The impact ofexercise on the cognitive functioning of healthy older adults: a systematic review and meta-analysis. Ageing Res Rev. 2014;16:12-31. ** Extensive review and meta-analysis regarding the cognitive effects of exercise in elderly subjects 13. Law LL, Barnett F, Yau MK, Gray MA. Effects of combined cognitive and exerciseinterventions on cognition in older adults with and without cognitive impairment: a systematic review. Ageing Res Rev. 2014;15:61-75. 14. Hindin SB, Zelinski EM. Extended practice and aerobic exercise interventions benefituntrained cognitive outcomes in older adults: a meta-analysis. J Am Geriatr Soc. 2012;60(1):136-41. 15. Larson EB, Wang L, Bowen JD, McCormick WC, Teri L, Crane P, et al. Exercise isassociated with reduced risk for incident dementia among persons 65 years of age and older. Ann Intern Med. 2006;144(2):73-81. 16. Hamer M, Chida Y. Physical activity and risk of neurodegenerative disease: a systematicreview of prospective evidence. Psychol Med. 2009;39(1):3-11. 17. Geda YE, Roberts RO, Knopman DS, Christianson TJ, Pankratz VS, Ivnik RJ, et al.Physical exercise, aging, and mild cognitive impairment: a population-based study. Arch Neurol. 2010;67(1):80-6. 18. Xu Q, Park Y, Huang X, Hollenbeck A, Blair A, Schatzkin A, et al. Physical activities andfuture risk of Parkinson disease. Neurology. 2010;75(4):341-8. 19. Yang F, Trolle Lagerros Y, Bellocco R, Adami HO, Fang F, Pedersen NL, et al. Physicalactivity and risk of Parkinson's disease in the Swedish National March Cohort. Brain. 2015;138(Pt 2):269-75. 20. Groot C, Hooghiemstra AM, Raijmakers PG, van Berckel BN, Scheltens P, Scherder EJ,et al. The effect of physical activity on cognitive function in patients with dementia: A meta-analysis of randomized control trials. Ageing Res Rev. 2016;25:13-23. 21. Ströhle A, Schmidt DK, Schultz F, Fricke N, Staden T, Hellweg R, et al. Drug andExercise Treatment of Alzheimer Disease and Mild Cognitive Impairment: A Systematic Review and Meta-Analysis of Effects on Cognition in Randomized Controlled Trials. Am J Geriatr Psychiatry. 2015;23(12):1234-49. ** Extensive review and meta-analysis regarding the cognitive effects of exercise in AD and MCI

22. Hindle JV, Petrelli A, Clare L, Kalbe E. Nonpharmacological enhancement of cognitivefunction in Parkinson's disease: a systematic review. Mov Disord. 2013;28(8):1034-49. 23. Wang C, Yu JT, Wang HF, Tan CC, Meng XF, Tan L. Non-pharmacological interventionsfor patients with mild cognitive impairment: a meta-analysis of randomized controlled trials of cognition-based and exercise interventions. J Alzheimers Dis. 2014;42(2):663-78. 24. Ohman H, Savikko N, Strandberg TE, Pitkala KH. Effect of physical exercise on cognitiveperformance in older adults with mild cognitive impairment or dementia: a systematic review. Dement Geriatr Cogn Disord. 2014;38(5-6):347-65. 25. Paillard T, Rolland Y, de Souto Barreto P. Protective Effects of Physical Exercise inAlzheimer's Disease and Parkinson's Disease: A Narrative Review. J Clin Neurol. 2015;11(3):212-9. 26. Bherer L, Erickson KI, Liu-Ambrose T. A review of the effects of physical activity andexercise on cognitive and brain functions in older adults. J Aging Res. 2013;2013:657508. 27. DeFilipe J. The evolution of the brain, the human nature of cortical circuits, andintellectual creativity. Frontiers in Neuroanatomy. 2011;5(29):1-17. 28. Bayés A, Collins MO, Croning MD, van de Lagemaat LN, Choudhary JS, Grant SG.Comparative study of human and mouse postsynaptic proteomes finds high compositional conservation and abundance differences for key synaptic proteins. PLoS One. 2012;7[10):e46683. 29. Vivar C, Potter MC, van Praag H. All about running: synaptic plasticity, growth factorsand adult hippocampal neurogenesis. Curr Top Behav Neurosci. 2013;15:189-210. 30. van Praag H, Christie BR, Sejnowski TJ, Gage FH. Running enhances neurogenesis,learning, and long-term potentiation in mice. Proc Natl Acad Sci U S A. 1999;96[23):13427-31. 31. van Praag H, Kempermann G, Gage FH. Running increases cell proliferation andneurogenesis in the adult mouse dentate gyrus. Nat Neurosci. 1999;2(3):266-70. 32. Kronenberg G, Bick-Sander A, Bunk E, Wolf C, Ehninger D, Kempermann G. Physicalexercise prevents age-related decline in precursor cell activity in the mouse dentate gyrus. Neurobiol Aging. 2006;27(10):1505-13. 33. Kohman RA, Clark PJ, Deyoung EK, Bhattacharya TK, Venghaus CE, Rhodes JS.Voluntary wheel running enhances contextual but not trace fear conditioning. Behav Brain Res. 2012;226(1):1-7. 34. Uysal N, Tugyan K, Kayatekin BM, Acikgoz O, Bagriyanik HA, Gonenc S, et al. Theeffects of regular aerobic exercise in adolescent period on hippocampal neuron density, apoptosis and spatial memory. Neurosci Lett. 2005;383(3):241-5. 35. Hotting K, Roder B. Beneficial effects of physical exercise on neuroplasticity andcognition. Neurosci Biobehav Rev. 2013;37(9 Pt B):2243-57. 36. Colcombe SJ, Erickson KI, Scalf PE, Kim JS, Prakash R, McAuley E, et al. Aerobicexercise training increases brain volume in aging humans. J Gerontol A Biol Sci Med Sci. 2006;61(11):1166-70. 37. Phillips C, Baktir MA, Srivatsan M, Salehi A. Neuroprotective effects of physical activityon the brain: a closer look at trophic factor signaling. Front Cell Neurosci. 2014;8:170. 38. Monteiro-Junior RS, Cevada T, Oliveira BR, Lattari E, Portugal EM, Carvalho A, et al. Weneed to move more: Neurobiological hypotheses of physical exercise as a treatment for Parkinson's disease. Med Hypotheses. 2015;85(5):537-41.

39. Cotman CW, Berchtold NC, Christie LA. Exercise builds brain health: key roles of growthfactor cascades and inflammation. Trends Neurosci. 2007;30(9):464-72. 40. Kirk-Sanchez NJ, McGough EL. Physical exercise and cognitive performance in theelderly: current perspectives. Clin Interv Aging. 2014;9:51-62. 41. Vilar M, Mira H. Regulation of Neurogenesis by Neurotrophins during Adulthood:Expected and Unexpected Roles. Front Neurosci. 2016;10:26. * Updated and extensive review regarding the role of trophic factors in the neurogenesis mechanisms of adult subjects 42. Lu B, Chow A. Neurotrophins and hippocampal synaptic transmission and plasticity. JNeurosci Res. 1999;58(1):76-87. 43. Nakata H, Nakamura S. Brain-derived neurotrophic factor regulates AMPA receptortrafficking to post-synaptic densities via IP3R and TRPC calcium signaling. FEBS Lett. 2007;581(10):2047-54. 44. Schinder AF, Poo M. The neurotrophin hypothesis for synaptic plasticity. TrendsNeurosci. 2000;23(12):639-45. 45. Korte M, Carroll P, Wolf E, Brem G, Thoenen H, Bonhoeffer T. Hippocampal long-termpotentiation is impaired in mice lacking brain-derived neurotrophic factor. Proc Natl Acad Sci U S A. 1995;92(19):8856-60. 46. Barde YA. Neurotrophins: a family of proteins supporting the survival of neurons. ProgClin Biol Res. 1994;390:45-56. 47. Reichardt LF. Neurotrophin-regulated signalling pathways. Philos Trans R Soc Lond BBiol Sci. 2006;361(1473):1545-64. 48. Lindvall O, Kokaia Z, Bengzon J, Elmér E, Kokaia M. Neurotrophins and brain insults.Trends Neurosci. 1994;17(11):490-6. 49. Pringle AK, Sundstrom LE, Wilde GJ, Williams LR, Iannotti F. Brain-derived neurotrophicfactor, but not neurotrophin-3, prevents ischaemia-induced neuronal cell death in organotypic rat hippocampal slice cultures. Neurosci Lett. 1996;211(3):203-6. 50. Oliveira SL, Pillat MM, Cheffer A, Lameu C, Schwindt TT, Ulrich H. Functions ofneurotrophins and growth factors in neurogenesis and brain repair. Cytometry A. 2013;83(1):76- 89. 51. Chen Y, Zeng J, Cen L, Wang X, Yao G, Wang W, et al. Multiple roles of the p75neurotrophin receptor in the nervous system. J Int Med Res. 2009;37(2):281-8. 52. Zhang L, Jiang H, Hu Z. Concentration-dependent effect of nerve growth factor on cellfate determination of neural progenitors. Stem Cells Dev. 2011;20(10):1723-31. 53. Pascual A, Hidalgo-Figueroa M, Gómez-Díaz R, López-Barneo J. GDNF and protectionof adult central catecholaminergic neurons. J Mol Endocrinol. 2011;46(3):R83-92. 54. Cotman CW, Berchtold NC. Exercise: a behavioral intervention to enhance brain healthand plasticity. Trends Neurosci. 2002;25(6):295-301. 55. Cotman CW, Berchtold NC. Physical activity and the maintenance of cognition: learningfrom animal models. Alzheimers Dement. 2007;3(2 Suppl):S30-7. 56. Espinet C, Gonzalo H, Fleitas C, Menal MJ, Egea J. Oxidative stress andneurodegenerative diseases: a neurotrophic approach. Curr Drug Targets. 2015;16(1):20-30. 57. Adachi N, Numakawa T, Richards M, Nakajima S, Kunugi H. New insight in expression,transport, and secretion of brain-derived neurotrophic factor: Implications in brain-related diseases. World J Biol Chem. 2014;5(4):409-28.

58. Biojone C, Casarotto PC, Joca SR, Castren E. Interplay Between Nitric Oxide and Brain-Derived Neurotrophic Factor in Neuronal Plasticity. CNS Neurol Disord Drug Targets. 2015;14(8):979-87. 59. Petzold A, Psotta L, Brigadski T, Endres T, Lessmann V. Chronic BDNF deficiency leadsto an age-dependent impairment in spatial learning. Neurobiol Learn Mem. 2015;120:52-60. 60. Komulainen P, Pedersen M, Hanninen T, Bruunsgaard H, Lakka TA, Kivipelto M, et al.BDNF is a novel marker of cognitive function in ageing women: the DR's EXTRA Study. Neurobiol Learn Mem. 2008;90(4):596-603. 61. Kennedy KM, Reese ED, Horn MM, Sizemore AN, Unni AK, Meerbrey ME, et al. BDNFval66met polymorphism affects aging of multiple types of memory. Brain Res. 2015;1612:104-17. 62. Murer MG, Yan Q, Raisman-Vozari R. Brain-derived neurotrophic factor in the controlhuman brain, and in Alzheimer's disease and Parkinson's disease. Prog Neurobiol. 2001;63(1):71-124. 63. Ventriglia M, Zanardini R, Bonomini C, Zanetti O, Volpe D, Pasqualetti P, et al. Serumbrain-derived neurotrophic factor levels in different neurological diseases. Biomed Res Int. 2013;2013:901082. 64. Lu B, Nagappan G, Guan X, Nathan PJ, Wren P. BDNF-based synaptic repair as adisease-modifying strategy for neurodegenerative diseases. Nat Rev Neurosci. 2013;14(6):401-16. 65. Lommatzsch M, Zingler D, Schuhbaeck K, Schloetcke K, Zingler C, Schuff-Werner P, etal. The impact of age, weight and gender on BDNF levels in human platelets and plasma. Neurobiol Aging. 2005;26(1):115-23. 66. Li G, Peskind ER, Millard SP, Chi P, Sokal I, Yu CE, et al. Cerebrospinal fluidconcentration of brain-derived neurotrophic factor and cognitive function in non-demented subjects. PLoS One. 2009;4(5):e5424. 67. Erickson KI, Prakash RS, Voss MW, Chaddock L, Heo S, McLaren M, et al. Brain-derivedneurotrophic factor is associated with age-related decline in hippocampal volume. J Neurosci. 2010;30(15):5368-75. 68. Turana Y, Ranakusuma TA, Purba JS, Amir N, Ahmad SA, Machfoed MH, et al.Enhancing Diagnostic Accuracy of aMCI in the Elderly: Combination of Olfactory Test, Pupillary Response Test, BDNF Plasma Level, and APOE Genotype. Int J Alzheimers Dis. 2014;2014:912586. 69. Peng S, Wuu J, Mufson EJ, Fahnestock M. Precursor form of brain-derived neurotrophicfactor and mature brain-derived neurotrophic factor are decreased in the pre-clinical stages of Alzheimer's disease. J Neurochem. 2005;93(6):1412-21. 70. Forlenza OV, Diniz BS, Teixeira AL, Ojopi EB, Talib LL, Mendonca VA, et al. Effect ofbrain-derived neurotrophic factor Val66Met polymorphism and serum levels on the progression of mild cognitive impairment. World J Biol Psychiatry. 2010;11(6):774-80. 71. Forlenza OV, Diniz BS, Teixeira AL, Radanovic M, Talib LL, Rocha NP, et al. LowerCerebrospinal Fluid Concentration of Brain-Derived Neurotrophic Factor Predicts Progression from Mild Cognitive Impairment to Alzheimer's Disease. Neuromolecular Med. 2015;17(3):326-32. 72. Song JH, Yu JT, Tan L. Brain-Derived Neurotrophic Factor in Alzheimer's Disease: Risk,Mechanisms, and Therapy. Mol Neurobiol. 2015;52(3):1477-93.

73. O'Bryant SE, Hobson V, Hall JR, Waring SC, Chan W, Massman P, et al. Brain-derivedneurotrophic factor levels in Alzheimer's disease. J Alzheimers Dis. 2009;17(2):337-41. 74. Budni J, Bellettini-Santos T, Mina F, Garcez ML, Zugno AI. The involvement of BDNF,NGF and GDNF in aging and Alzheimer's disease. Aging Dis. 2015;6(5):331-41. 75. Phillips HS, Hains JM, Armanini M, Laramee GR, Johnson SA, Winslow JW. BDNFmRNA is decreased in the hippocampus of individuals with Alzheimer's disease. Neuron. 1991;7(5):695-702. 76. Hock C, Heese K, Hulette C, Rosenberg C, Otten U. Region-specific neurotrophinimbalances in Alzheimer disease: decreased levels of brain-derived neurotrophic factor and increased levels of nerve growth factor in hippocampus and cortical areas. Arch Neurol. 2000;57(6):846-51. 77. Connor B, Young D, Yan Q, Faull RL, Synek B, Dragunow M. Brain-derived neurotrophicfactor is reduced in Alzheimer's disease. Brain Res Mol Brain Res. 1997;49(1-2):71-81. 78. Michalski B, Fahnestock M. Pro-brain-derived neurotrophic factor is decreased in parietalcortex in Alzheimer's disease. Brain Res Mol Brain Res. 2003;111(1-2):148-54. 79. Holsinger RM, Schnarr J, Henry P, Castelo VT, Fahnestock M. Quantitation of BDNFmRNA in human parietal cortex by competitive reverse transcription-polymerase chain reaction: decreased levels in Alzheimer's disease. Brain Res Mol Brain Res. 2000;76(2):347-54. 80. Narisawa-Saito M, Wakabayashi K, Tsuji S, Takahashi H, Nawa H. Regional specificity ofalterations in NGF, BDNF and NT-3 levels in Alzheimer's disease. Neuroreport. 1996;7(18):2925-8. 81. Islam O, Loo TX, Heese K. Brain-derived neurotrophic factor (BDNF) has proliferativeeffects on neural stem cells through the truncated TRK-B receptor, MAP kinase, AKT, and STAT-3 signaling pathways. Curr Neurovasc Res. 2009;6(1):42-53. 82. Chao MV, Hempstead BL. p75 and Trk: a two-receptor system. Trends Neurosci.1995;18(7):321-6. 83. Teng HK, Teng KK, Lee R, Wright S, Tevar S, Almeida RD, et al. ProBDNF inducesneuronal apoptosis via activation of a receptor complex of p75NTR and sortilin. J Neurosci. 2005;25(22):5455-63. 84. Hempstead BL. The many faces of p75NTR. Curr Opin Neurobiol. 2002;12(3):260-7.85. Mufson EJ, Ikonomovic MD, Styren SD, Counts SE, Wuu J, Leurgans S, et al.Preservation of brain nerve growth factor in mild cognitive impairment and Alzheimer disease. Arch Neurol. 2003;60(8):1143-8. 86. Chu Y, Cochran EJ, Bennett DA, Mufson EJ, Kordower JH. Down-regulation of trkAmRNA within nucleus basalis neurons in individuals with mild cognitive impairment and Alzheimer's disease. J Comp Neurol. 2001;437(3):296-307. 87. Counts SE, Nadeem M, Wuu J, Ginsberg SD, Saragovi HU, Mufson EJ. Reduction ofcortical TrkA but not p75(NTR) protein in early-stage Alzheimer's disease. Ann Neurol. 2004;56(4):520-31. 88. Mufson EJ, Lavine N, Jaffar S, Kordower JH, Quirion R, Saragovi HU. Reduction in p140-TrkA receptor protein within the nucleus basalis and cortex in Alzheimer's disease. Exp Neurol. 1997;146(1):91-103.

89. Coelho FG, Vital TM, Stein AM, Arantes FJ, Rueda AV, Camarini R, et al. Acute aerobicexercise increases brain-derived neurotrophic factor levels in elderly with Alzheimer's disease. J Alzheimers Dis. 2014;39(2):401-8. 90. Laske C, Stransky E, Leyhe T, Eschweiler GW, Maetzler W, Wittorf A, et al. BDNF serumand CSF concentrations in Alzheimer's disease, normal pressure hydrocephalus and healthy controls. J Psychiatr Res. 2007;41(5):387-94. 91. Platenik J, Fisar Z, Buchal R, Jirak R, Kitzlerova E, Zverova M, et al. GSK3beta, CREB,and BDNF in peripheral blood of patients with Alzheimer's disease and depression. Prog Neuropsychopharmacol Biol Psychiatry. 2014;50:83-93. 92. Leyhe T, Stransky E, Eschweiler GW, Buchkremer G, Laske C. Increase of BDNF serumconcentration during donepezil treatment of patients with early Alzheimer's disease. Eur Arch Psychiatry Clin Neurosci. 2008;258(2):124-8. 93. Angelucci F, Spalletta G, di Iulio F, Ciaramella A, Salani F, Colantoni L, et al. Alzheimer'sdisease (AD) and Mild Cognitive Impairment (MCI) patients are characterized by increased BDNF serum levels. Curr Alzheimer Res. 2010;7(1):15-20. 94. Laske C, Stransky E, Leyhe T, Eschweiler GW, Wittorf A, Richartz E, et al. Stage-dependent BDNF serum concentrations in Alzheimer's disease. J Neural Transm (Vienna). 2006;113(9):1217-24. 95. Parain K, Murer MG, Yan Q, Faucheux B, Agid Y, Hirsch E, et al. Reduced expression ofbrain-derived neurotrophic factor protein in Parkinson's disease substantia nigra. Neuroreport. 1999;10(3):557-61. 96. Mogi M, Togari A, Kondo T, Mizuno Y, Komure O, Kuno S, et al. Brain-derived growthfactor and nerve growth factor concentrations are decreased in the substantia nigra in Parkinson's disease. Neurosci Lett. 1999;270(1):45-8. 97. Scalzo P, Kummer A, Bretas TL, Cardoso F, Teixeira AL. Serum levels of brain-derivedneurotrophic factor correlate with motor impairment in Parkinson's disease. J Neurol. 2010;257(4):540-5. 98. Castellano V, White LJ. Serum brain-derived neurotrophic factor response to aerobicexercise in multiple sclerosis. J Neurol Sci. 2008;269(1-2):85-91. 99. Gold SM, Schulz KH, Hartmann S, Mladek M, Lang UE, Hellweg R, et al. Basal serumlevels and reactivity of nerve growth factor and brain-derived neurotrophic factor to standardized acute exercise in multiple sclerosis and controls. J Neuroimmunol. 2003;138(1-2):99-105. 100. Stadelmann C, Kerschensteiner M, Misgeld T, Bruck W, Hohlfeld R, Lassmann H. BDNF and gp145trkB in multiple sclerosis brain lesions: neuroprotective interactions between immune and neuronal cells? Brain. 2002;125(Pt 1):75-85. 101. Sarchielli P, Greco L, Stipa A, Floridi A, Gallai V. Brain-derived neurotrophic factor in patients with multiple sclerosis. J Neuroimmunol. 2002;132(1-2):180-8. 102. Mashayekhi F, Salehi Z, Jamalzadeh HR. Quantitative analysis of cerebrospinal fluid brain derived neurotrophic factor in the patients with multiple sclerosis. Acta Medica (Hradec Kralove). 2012;55(2):83-6. 103. Sopova K, Gatsiou K, Stellos K, Laske C. Dysregulation of neurotrophic and haematopoietic growth factors in Alzheimer's disease: from pathophysiology to novel treatment strategies. Curr Alzheimer Res. 2014;11(1):27-39.

104. Perovic M, Tesic V, Mladenovic Djordjevic A, Smiljanic K, Loncarevic-Vasiljkovic N, Ruzdijic S, et al. BDNF transcripts, proBDNF and proNGF, in the cortex and hippocampus throughout the life span of the rat. Age (Dordr). 2013;35(6):2057-70. 105. Hasenohrl RU, Soderstrom S, Mohammed AH, Ebendal T, Huston JP. Reciprocal changes in expression of mRNA for nerve growth factor and its receptors TrkA and LNGFR in brain of aged rats in relation to maze learning deficits. Exp Brain Res. 1997;114(2):205-13. 106. Murase K, Nabeshima T, Robitaille Y, Quirion R, Ogawa M, Hayashi K. NGF level of is not decreased in the serum, brain-spinal fluid, hippocampus, or parietal cortex of individuals with Alzheimer's disease. Biochem Biophys Res Commun. 1993;193(1):198-203. 107. Faria MC, Goncalves GS, Rocha NP, Moraes EN, Bicalho MA, Gualberto Cintra MT, et al. Increased plasma levels of BDNF and inflammatory markers in Alzheimer's disease. J Psychiatr Res. 2014;53:166-72. 108. Blasko I, Lederer W, Oberbauer H, Walch T, Kemmler G, Hinterhuber H, et al. Measurement of thirteen biological markers in CSF of patients with Alzheimer's disease and other dementias. Dement Geriatr Cogn Disord. 2006;21(1):9-15. 109. Peng S, Wuu J, Mufson EJ, Fahnestock M. Increased proNGF levels in subjects with mild cognitive impairment and mild Alzheimer disease. J Neuropathol Exp Neurol. 2004;63(6):641-9. 110. Ferreira D, Westman E, Eyjolfsdottir H, Almqvist P, Lind G, Linderoth B, et al. Brain changes in Alzheimer's disease patients with implanted encapsulated cells releasing nerve growth factor. J Alzheimers Dis. 2015;43(3):1059-72. 111. d'Anglemont de Tassigny X, Pascual A, Lopez-Barneo J. GDNF-based therapies, GDNF-producing interneurons, and trophic support of the dopaminergic nigrostriatal pathway. Implications for Parkinson's disease. Front Neuroanat. 2015;9:10. 112. Pertusa M, Garcia-Matas S, Mammeri H, Adell A, Rodrigo T, Mallet J, et al. Expression of GDNF transgene in astrocytes improves cognitive deficits in aged rats. Neurobiol Aging. 2008;29(9):1366-79. 113. Matsunaga W, Isobe K, Shirokawa T. Involvement of neurotrophic factors in aging of noradrenergic innervations in hippocampus and frontal cortex. Neurosci Res. 2006;54(4):313-8. 114. Airavaara M, Pletnikova O, Doyle ME, Zhang YE, Troncoso JC, Liu QR. Identification of novel GDNF isoforms and cis-antisense GDNFOS gene and their regulation in human middle temporal gyrus of Alzheimer disease. J Biol Chem. 2011;286(52):45093-102. 115. Forlenza OV, Miranda AS, Guimar I, Talib LL, Diniz BS, Gattaz WF, et al. Decreased Neurotrophic Support is Associated with Cognitive Decline in Non-Demented Subjects. J Alzheimers Dis. 2015;46(2):423-9. 116. Marksteiner J, Kemmler G, Weiss EM, Knaus G, Ullrich C, Mechtcheriakov S, et al. Five out of 16 plasma signaling proteins are enhanced in plasma of patients with mild cognitive impairment and Alzheimer's disease. Neurobiol Aging. 2011;32(3):539-40. 117. Straten G, Saur R, Laske C, Gasser T, Annas P, Basun H, et al. Influence of lithium treatment on GDNF serum and CSF concentrations in patients with early Alzheimer's disease. Curr Alzheimer Res. 2011;8(8):853-9. 118. Mogi M, Togari A, Kondo T, Mizuno Y, Kogure O, Kuno S, et al. Glial cell line-derived neurotrophic factor in the substantia nigra from control and parkinsonian brains. Neurosci Lett. 2001;300(3):179-81.

119. Chauhan NB, Siegel GJ, Lee JM. Depletion of glial cell line-derived neurotrophic factor in substantia nigra neurons of Parkinson's disease brain. J Chem Neuroanat. 2001;21(4):277-88. 120. Boado RJ, Pardridge WM. Comparison of blood-brain barrier transport of glial-derived neurotrophic factor (GDNF) and an IgG-GDNF fusion protein in the rhesus monkey. Drug Metab Dispos. 2009;37(12):2299-304. 121. Patel NK, Bunnage M, Plaha P, Svendsen CN, Heywood P, Gill SS. Intraputamenal infusion of glial cell line-derived neurotrophic factor in PD: a two-year outcome study. Ann Neurol. 2005;57(2):298-302. 122. Slevin JT, Gerhardt GA, Smith CD, Gash DM, Kryscio R, Young B. Improvement of bilateral motor functions in patients with Parkinson disease through the unilateral intraputaminal infusion of glial cell line-derived neurotrophic factor. J Neurosurg. 2005;102(2):216-22. 123. de la Monte SM, Wands JR. Review of insulin and insulin-like growth factor expression, signaling, and malfunction in the central nervous system: relevance to Alzheimer's disease. J Alzheimers Dis. 2005;7(1):45-61. 124. Aleman A, Torres-Aleman I. Circulating insulin-like growth factor I and cognitive function: neuromodulation throughout the lifespan. Prog Neurobiol. 2009;89(3):256-65. 125. van Dam PS, Aleman A. Insulin-like growth factor-I, cognition and brain aging. Eur J Pharmacol. 2004;490(1-3):87-95. 126. Sonntag WE, Ramsey M, Carter CS. Growth hormone and insulin-like growth factor-1 (IGF-1) and their influence on cognitive aging. Ageing Res Rev. 2005;4(2):195-212. 127. Westwood AJ, Beiser A, Decarli C, Harris TB, Chen TC, He XM, et al. Insulin-like growth factor-1 and risk of Alzheimer dementia and brain atrophy. Neurology. 2014;82(18):1613-9. 128. Rivera EJ, Goldin A, Fulmer N, Tavares R, Wands JR, de la Monte SM. Insulin and insulin-like growth factor expression and function deteriorate with progression of Alzheimer's disease: link to brain reductions in acetylcholine. J Alzheimers Dis. 2005;8(3):247-68. 129. Piriz J, Muller A, Trejo JL, Torres-Aleman I. IGF-I and the aging mammalian brain. Exp Gerontol. 2011;46(2-3):96-9. 130. Hertze J, Nagga K, Minthon L, Hansson O. Changes in cerebrospinal fluid and blood plasma levels of IGF-II and its binding proteins in Alzheimer's disease: an observational study. BMC Neurol. 2014;14:64. 131. Voss MW, Erickson KI, Prakash RS, Chaddock L, Kim JS, Alves H, et al. Neurobiological markers of exercise-related brain plasticity in older adults. Brain Behav Immun. 2013;28:90-9. 132. Jensen CS, Hasselbalch SG, Waldemar G, Simonsen AH. Biochemical Markers of Physical Exercise on Mild Cognitive Impairment and Dementia: Systematic Review and Perspectives. Front Neurol. 2015;6:187. ** Extensive review and updated perspective regarding the biological pathways of exercise in MCI and dementia patients.

133. Ang ET, Gomez-Pinilla F. Potential therapeutic effects of exercise to the brain. Curr Med Chem. 2007;14(24):2564-71. 134. Portugal EM, Vasconcelos PG, Souza R, Lattari E, Monteiro-Junior RS, Machado S, et al. Aging process, cognitive decline and Alzheimer`s disease: can strength training modulate these responses? CNS Neurol Disord Drug Targets. 2015;14(9):1209-13.

135. Szuhany KL, Bugatti M, Otto MW. A meta-analytic review of the effects of exercise on brain-derived neurotrophic factor. J Psychiatr Res. 2014;60C:56-64. ** Meta-analytic review of the effects of acute and chronic exercise on peripheral BDNF levels in several populations 136. Zoladz JA, Pilc A. The effect of physical activity on the brain derived neurotrophic factor: from animal to human studies. J Physiol Pharmacol. 2010;61(5):533-41. 137. Huang T, Larsen KT, Ried-Larsen M, Møller NC, Andersen LB. The effects of physical activity and exercise on brain-derived neurotrophic factor in healthy humans: A review. Scand J Med Sci Sports. 2014;24(1):1-10. 138. Coelho FG, Gobbi S, Andreatto CA, Corazza DI, Pedroso RV, Santos-Galduroz RF. Physical exercise modulates peripheral levels of brain-derived neurotrophic factor (BDNF): a systematic review of experimental studies in the elderly. Arch Gerontol Geriatr. 2013;56(1):10-5. ** Systematic review on the effects of exercise on peripheral BDNF levels in elderly subjects 139. Laske C, Banschbach S, Stransky E, Bosch S, Straten G, Machann J, et al. Exercise-induced normalization of decreased BDNF serum concentration in elderly women with remitted major depression. Int J Neuropsychopharmacol. 2010;13(5):595-602. 140. Coelho FM, Pereira DS, Lustosa LP, Silva JP, Dias JM, Dias RC, et al. Physical therapy intervention (PTI) increases plasma brain-derived neurotrophic factor (BDNF) levels in non-frail and pre-frail elderly women. Arch Gerontol Geriatr. 2012;54(3):415-20. 141. Anderson-Hanley C, Arciero PJ, Brickman AM, Nimon JP, Okuma N, Westen SC, et al. Exergaming and older adult cognition: a cluster randomized clinical trial. Am J Prev Med. 2012;42(2):109-19. 142. Ruscheweyh R, Willemer C, Krüger K, Duning T, Warnecke T, Sommer J, et al. Physical activity and memory functions: an interventional study. Neurobiol Aging. 2011;32(7):1304-19. 143. Baker LD, Frank LL, Foster-Schubert K, Green PS, Wilkinson CW, McTiernan A, et al. Aerobic exercise improves cognition for older adults with glucose intolerance, a risk factor for Alzheimer's disease. J Alzheimers Dis. 2010;22(2):569-79. 144. Erickson KI, Voss MW, Prakash RS, Basak C, Szabo A, Chaddock L, et al. Exercise training increases size of hippocampus and improves memory. Proc Natl Acad Sci U S A. 2011;108(7):3017-22. * Clinical trial which associates a 1-year aerobic exercise intervention with hippocampus increase and BDNF levels enhancement. 145. Nascimento CM, Pereira JR, Pires de Andrade L, Garuffi M, Ayan C, Kerr DS, et al. Physical exercise improves peripheral BDNF levels and cognitive functions in mild cognitive impairment elderly with different bdnf Val66Met genotypes. J Alzheimers Dis. 2015;43(1):81-91. 146. Nascimento CM, Pereira JR, de Andrade LP, Garuffi M, Talib LL, Forlenza OV, et al. Physical exercise in MCI elderly promotes reduction of pro-inflammatory cytokines and improvements on cognition and BDNF peripheral levels. Curr Alzheimer Res. 2014;11(8):799-805. 147. Baker LD, Frank LL, Foster-Schubert K, Green PS, Wilkinson CW, McTiernan A, et al. Effects of aerobic exercise on mild cognitive impairment: a controlled trial. Arch Neurol. 2010;67(1):71-9. 148. Zoladz JA, Majerczak J, Zeligowska E, Mencel J, Jaskolski A, Jaskolska A, et al. Moderate-intensity interval training increases serum brain-derived neurotrophic factor level and decreases inflammation in Parkinson's disease patients. J Physiol Pharmacol. 2014;65(3):441-8.

149. Marusiak J, Zeligowska E, Mencel J, Kisiel-Sajewicz K, Majerczak J, Zoladz JA, et al. Interval training-induced alleviation of rigidity and hypertonia in patients with Parkinson's disease is accompanied by increased basal serum brain-derived neurotrophic factor. J Rehabil Med. 2015;47(4):372-5. 150. Bansi J, Bloch W, Gamper U, Kesselring J. Training in MS: influence of two different endurance training protocols (aquatic versus overland) on cytokine and neurotrophin concentrations during three week randomized controlled trial. Mult Scler. 2013;19(5):613-21. 151. Schulz KH, Gold SM, Witte J, Bartsch K, Lang UE, Hellweg R, et al. Impact of aerobic training on immune-endocrine parameters, neurotrophic factors, quality of life and coordinative function in multiple sclerosis. J Neurol Sci. 2004;225(1-2):11-8. 152. Suzuki T, Shimada H, Makizako H, Doi T, Yoshida D, Ito K, et al. A randomized controlled trial of multicomponent exercise in older adults with mild cognitive impairment. PLoS One. 2013;8(4):e61483. 153. Trejo JL, Carro E, Torres-Aleman I. Circulating insulin-like growth factor I mediates exercise-induced increases in the number of new neurons in the adult hippocampus. J Neurosci. 2001;21(5):1628-34. 154. Carro E, Nunez A, Busiguina S, Torres-Aleman I. Circulating insulin-like growth factor I mediates effects of exercise on the brain. J Neurosci. 2000;20(8):2926-33. 155. Carro E, Trejo JL, Spuch C, Bohl D, Heard JM, Torres-Aleman I. Blockade of the insulin-like growth factor I receptor in the choroid plexus originates Alzheimer's-like neuropathology in rodents: new cues into the human disease? Neurobiol Aging. 2006;27(11):1618-31. 156. Cassilhas RC, Viana VA, Grassmann V, Santos RT, Santos RF, Tufik S, et al. The impact of resistance exercise on the cognitive function of the elderly. Med Sci Sports Exerc. 2007;39(8):1401-7. 157. Nishida Y, Matsubara T, Tobina T, Shindo M, Tokuyama K, Tanaka K, et al. Effect of low-intensity aerobic exercise on insulin-like growth factor-I and insulin-like growth factor-binding proteins in healthy men. Int J Endocrinol. 2010;2010. 158. Radak Z, Toldy A, Szabo Z, Siamilis S, Nyakas C, Silye G, et al. The effects of training and detraining on memory, neurotrophins and oxidative stress markers in rat brain. Neurochem Int. 2006;49(4):387-92. 159. Chae CH, Jung SL, An SH, Park BY, Kim TW, Wang SW, et al. Swimming exercise stimulates neuro-genesis in the subventricular zone via increase in synapsin I and nerve growth factor levels. Biol Sport. 2014;31(4):309-14. 160. Lopez-Lopez C, LeRoith D, Torres-Aleman I. Insulin-like growth factor I is required for vessel remodeling in the adult brain. Proc Natl Acad Sci U S A. 2004;101(26):9833-8. 161. Lewin GR, Carter BD. Neurotrophic Factors. In: Rosenthal W, editor. Handbook of Experimental Pharmacology. 220. London: Springer; 2014. 162. Sharma HS, Cervós-Navarro J, Dey PK. Increased blood-brain barrier permeability following acute short-term swimming exercise in conscious normotensive young rats. Neurosci Res. 1991;10(3):211-21. 163. Bailey DM, Evans KA, McEneny J, Young IS, Hullin DA, James PE, et al. Exercise-induced oxidative-nitrosative stress is associated with impaired dynamic cerebral autoregulation and blood-brain barrier leakage. Exp Physiol. 2011;96(11):1196-207.

164. Poduslo JF, Curran GL. Permeability at the blood-brain and blood-nerve barriers of the neurotrophic factors: NGF, CNTF, NT-3, BDNF. Brain Res Mol Brain Res. 1996;36(2):280-6. 165. Pan W, Banks WA, Fasold MB, Bluth J, Kastin AJ. Transport of brain-derived neurotrophic factor across the blood-brain barrier. Neuropharmacology. 1998;37(12):1553-61. 166. Ide K, Secher NH. Cerebral blood flow and metabolism during exercise. Prog Neurobiol. 2000;61(4):397-414. 167. Querido JS, Sheel AW. Regulation of cerebral blood flow during exercise. Sports Med. 2007;37(9):765-82. 168. Rasmussen P, Brassard P, Adser H, Pedersen MV, Leick L, Hart E, et al. Evidence for a release of brain-derived neurotrophic factor from the brain during exercise. Exp Physiol. 2009;94(10):1062-9. 169. Berchtold NC, Chinn G, Chou M, Kesslak JP, Cotman CW. Exercise primes a molecular memory for brain-derived neurotrophic factor protein induction in the rat hippocampus. Neuroscience. 2005;133(3):853-61. 170. Knaepen K, Goekint M, Heyman EM, Meeusen R. Neuroplasticity - exercise-induced response of peripheral brain-derived neurotrophic factor: a systematic review of experimental studies in human subjects. Sports Med. 2010;40(9):765-801. 171. Fujimura H, Altar CA, Chen R, Nakamura T, Nakahashi T, Kambayashi J, et al. Brain-derived neurotrophic factor is stored in human platelets and released by agonist stimulation. Thromb Haemost. 2002;87(4):728-34. 172. Matthews VB, Aström MB, Chan MH, Bruce CR, Krabbe KS, Prelovsek O, et al. Brain-derived neurotrophic factor is produced by skeletal muscle cells in response to contraction and enhances fat oxidation via activation of AMP-activated protein kinase. Diabetologia. 2009;52(7):1409-18. 173. Butler AA, LeRoith D. Minireview: tissue-specific versus generalized gene targeting of the igf1 and igf1r genes and their roles in insulin-like growth factor physiology. Endocrinology. 2001;142(5):1685-8. 174. Pulford BE, Ishii DN. Uptake of circulating insulin-like growth factors (IGFs) into cerebrospinal fluid appears to be independent of the IGF receptors as well as IGF-binding proteins. Endocrinology. 2001;142(1):213-20. 175. Erickson KI, Miller DL, Roecklein KA. The aging hippocampus: interactions between exercise, depression, and BDNF. Neuroscientist. 2012;18(1):82-97. 176. Ivanov AD, Tukhbatova GR, Salozhin SV, Markevich VA. NGF but not BDNF overexpression protects hippocampal LTP from beta-amyloid-induced impairment. Neuroscience. 2015;289:114-22. 177. Nam JH, Leem E, Jeon MT, Jeong KH, Park JW, Jung UJ, et al. Induction of GDNF and BDNF by hRheb(S16H) transduction of SNpc neurons: neuroprotective mechanisms of hRheb(S16H) in a model of Parkinson's disease. Mol Neurobiol. 2015;51(2):487-99. 178. Nelson ME, Rejeski WJ, Blair SN, Duncan PW, Judge JO, King AC, et al. Physical activity and public health in older adults: recommendation from the American College of Sports Medicine and the American Heart Association. Med Sci Sports Exerc. 2007;39(8):1435-45. 179. Ala T. Donepezil may reduce Insulin-like Growth Factor-1 (IGF-1) levels in Alzheimer's disease. CNS Neurol Disord Drug Targets. 2015.

180. Sari Y, Khalil A. Monoamine Oxidase Inhibitors Extracted from Tobacco Smoke as Neuroprotective Factors for Potential Treatment of Parkinson's Disease. CNS Neurol Disord Drug Targets. 2015;14(6):777-85. 181. Zemva J, Schubert M. The role of neuronal insulin/insulin-like growth factor-1 signaling for the pathogenesis of Alzheimer's disease: possible therapeutic implications. CNS Neurol Disord Drug Targets. 2014;13(2):322-37. 182. KhorshidAhmad T, Acosta C, Cortes C, Lakowski TM, Gangadaran S, Namaka M. Transcriptional Regulation of Brain-Derived Neurotrophic Factor (BDNF) by Methyl CpG Binding Protein 2 (MeCP2): a Novel Mechanism for Re-Myelination and/or Myelin Repair Involved in the Treatment of Multiple Sclerosis (MS). Mol Neurobiol. 2015. 183. Rajasekar N, Nath C, Hanif K, Shukla R. Inhibitory Effect of Memantine on Streptozotocin-Induced Insulin Receptor Dysfunction, Neuroinflammation, Amyloidogenesis, and Neurotrophic Factor Decline in Astrocytes. Mol Neurobiol. 2015. 184. Nettiksimmons J, Simonsick EM, Harris T, Satterfield S, Rosano C, Yaffe K, et al. The associations between serum brain-derived neurotrophic factor, potential confounders, and cognitive decline: a longitudinal study. PLoS One. 2014;9(3):e91339.

Table 1: Clinical trials regarding exercise induced trophic factors changes in healthy elderly subjects or patients with non-degenerative diseases

Study Population Type of Exercise Sample Size

Mean Age

(years)

Gender

(% female)

Intervention Length

Session Frequency and

Duration Intensity of Exercise

Trophic Factor

Measures

Significant Trophic Factors Changes

Cassilhas and colleagues

(156) Elderly

Resistance Training:

Moderate Intensity (MRT)

High Intensity (HRT)

Stretching Exercise Control (SE)

MRT: 19

HRT: 20

SE: 23

MRT: 69

HRT: 68.4

SE: 67

No female participants 24 weeks

3d / week

60 min /session

MRT: 50% RM

HRT: 80% RM Serum ↑ IGF-I levels after intervention in MRT and HRT

Erickson and colleagues

(144)* Elderly

Walking Aerobic Exercise (AE)

Stretching Exercise Control (SE)

AE: 60

SE: 60

AE: 67.6

SE: 65.5

AE: 73%

SE: 60% 52 weeks

No info on frequency

40 min / session

AE: 50% - 75% HRmax Serum

No differences between groups after intervention

Greater BDNF changes were associated with increased hippocampus volume in AE participants

Ruscheweyh and colleagues

(142)* Elderly

Nordic Walking (NW)

Gymnastics (GM)

NW: 20

GM: 21

HC: 21

NW: 60.1

GM: 62.5

HC: 58.1

NW: 70%

GM: 62%

HC: 67%

24 weeks 3d / week

50 min / session

NW: 50 – 60% ME

GM: 30-40% ME Serum ↑ BDNF associated with increased levels of physical

activity (trend)

Anderson-Hanley and colleagues

(141)*

Elderly Cybercycle (CC)

Traditional Cycling (TC)

CC: 38

TC: 41

CC: 75.7

TC: 81.6

CC: 71%

TC: 87% 12 weeks

3d / week

45 min / session 60% HRmax Plasma ↑ BDNF levels in CC in comparison to TC

Voss and colleagues

(131)* Elderly

Walking Aerobic Exercise (AE)

Flexing, Toning & Balance (FTB)

AE: 30

FTB: 35

AE: 67.3

FTB: 65.4

AE: 73%

FTB: 71% 52 weeks 40 min / session

AE: 50 – 75% HRmax

FTB: 13-15 Borg Scale Serum

↓ IGF-I levels after intervention in both groups

No significant differences in BDNF and VEGF

Baker and colleagues

(143)*

Elderly with Glucose

Tolerance

Mulimodal Aerobic Exercise (AE)

Stretching Exercise Control (SE)

AE: 19

SE: 9

AE: 66

SE: 71

AE: 53%

SE: 90% 24 weeks

4d / week

45-60 min / session

AE: 75 - 85% HRmax

SE: < 50% HRmax Plasma No significant changes in BDNF and IGF-I levels in

both groups

Laske and colleagues

(139)

Depressed Elderly

Women (DE)

Acute Aerobic Exercise

(Incremental Treadmill Walking)

DE: 35

HC: 20

DE: 61.1

HC: 58.9

No male participants Single Session 30 min / session Until Volitional

Exhaustion Serum ↑ BDNF levels only in MDD patients

↓ BDNF after 30 min rest in both groups

Coelho and colleagues

(140)**

Elderly Women

(no frail and pre-frail)

Resistance Training

(knee flexors, extensors) 20 71 No male

participants 10 weeks 3d / week

60 min / session 50% - 75% MR Plasma

↑ Resting BDNF levels after intervention

No significant changes in GDNF or NGF

* Authors did not report information about baseline group differences or groups differed significantly at baseline regarding age and/or gender. However, these variables, as well as other demographic variable, were added as covariates to the analysis. ** The authors did not report any information regarding baseline group differences and did not had any variable as a covariate. HC: Healthy Control Group; HRmax: Maximum Heart Rate; RM: Repetition Maximum; MR: Maximal Resistance: ME: Maximal Exertion.

Table 2: Clinical trials regarding exercise induced trophic factors changes in patients with age-related neurodegenerative diseases

Study Population Type of Exercise Sample Size

Mean Age

(years)

Gender

(% female)

Intervention Length

Session Frequency and

Duration Intensity of Exercise

Trophic Factor

Measures

Significant Trophic Factors Changes

Baker et and colleagues (147)

Mild Cognitive

Impairment (MCI)

Aerobic Exercise (AE)

Stretching Exercise Control (SE)

AE: 19

SE: 10

AE: 67.95

SE: 72.6

AE: 53%

SE: 50% 24 weeks

4d / week

45-60 min / session

AE: 75 - 85% HRmax

SE: < 50% HRmax Plasma

↑ BDNF and IGF-I levels in male patients after AE

↓ BDNF levels in female patients of AE

Suzuki and colleagues (152)

Mild Cognitive

Impairment

Multimodal Group Exercise - aerobic, strength, etc (EG)

EG: 50

CG: 50

EG: 74.8

CG: 75.8

EG: 50%

CG: 48% 24 weeks

2d / week

90 min / session 60% HRmax Serum Higher BDNF levels at baseline was associated with

cognitive improvement

Nascimento and colleagues (146)

Mild Cognitive

Impairment

Multimodal Aerobic Exercise

Training (MCI-T & HC-T)

Control (MCI-C & HC)

MCI-T: 20

HC-T: 15

MCI-C: 17

HC. 15

MCI-T: 67.3

HC-T: 66.6

MCI-C: 68.5

HC: 68.1

MCI-T: 65%

HC-T:60%

MCI-C: 78.6

HC: 66.6%

16 weeks 3d / week

60 min / session 60 – 80% HRmax Plasma ↑ BDNF levels after intervention in MCI and HC

training groups

Nascimento and colleagues (145)

Mild Cognitive

Impairment

Multimodal Aerobic Exercise

(AE)

AE: 24

CG: 21

AE: 67.83

CG: 67.5

AE: 71%

CG: 71% 16 weeks

3d / week

60 min / session 60 – 80% HRmax Plasma

↑ BDNF levels after intervention only in AE

Only patients with wild-type genotype displayed significant improvements in BDNF

Coelho and colleagues (89)

Alzheimer

Disease (AD)

Acute Aerobic Exercise

(Sub-maximal)

AD: 21

HC: 18

AD: 76.3

HC: 74.6 No info Single Session No info Until 85% HRmax Plasma ↑ BDNF levels in both groups

Zoladz and colleagues (148)*

Parkinson Disease

Interval Training

(Cycling) 12 70 42% 8 weeks

3d / week

60 min / session 60-75% HRmax Serum ↑ BDNF levels after intervention

Marusiak and colleagues (149)*

Parkinson Disease

(PD)

Interval Training

(Cycling)

PD: 11

HC: 11

PD: 71

HC: 77

PD: 46%

HC: 82% 8 weeks

3d / week

60 min / session

PD: Mean 68% HRmax

HC: Mean 62% HRmax Serum ↑ BDNF levels only in PD patients

Gold and colleagues (99)

Multiple Sclerosis

(MS)

Acute Aerobic Exercise

(Bycicle Ergometry)

MS: 25

HC: 20

MS: 39.2

HC: 40.5

MS: 64%

HC: 70% Single Session 30 min / session 60% VO2Max Serum

↑ BDNF levels in both groups

↑ NGF levels in both groups (trend)

Schulz and colleagues (151)

Multiple Sclerosis

Individualized Aerobic Exercise (AE)

Wait-List Control Group (CG)

AE: 15

CG: 13

AE: 39

CG: 40

AE: 73%

CG: 62% 8 weeks

2d / week

30 min / session 75% MW Serum

↓ NGF levels in training group (trend)

No significant differences in BDNF

Castellano and colleagues (98)*

Multiple Sclerosis Cycling Aerobic Exercise

MS: 11

HC: 11

MS: 40

HC: 40

MS: 73%

HC: 73% 8 weeks

3d / week

30 min / session 60% VO2Max Serum

↑ Resting BDNF levels after 4 weeks

No significant changes in IGF-I after training

Bansi and colleagues (150)

Multiple Sclerosis

Endurance Cycling Training:

Land Ergometer (LE)

Aquatic Bike Training (AT)

LE: 28

AT: 24

LE: 52

AT: 50

EG: 64%

CG: 67% 3 weeks

5d / week

30 min / session

70% HRmax

60% VO2Max Serum

↑ BDNF after single bout of exercise in both groups

↑ Resting BNDF levels after intervention in AT

↑ Resting NGF after intervention in AT (trend)

* The authors did not report any information regarding baseline group differences and did not had any variable as a covariate. HC: Healthy Control Group; CG: Patient Control Group; HRmax: Maximum Heart Rate; VO2Max: Maximal Oxygen Uptake; MW: Maximal Watts.