The Effect Of Physical Exercise On Cognitive Impairment in Neurodegenerative Disease: From Pathophysiology To Clinical And Rehabilitative Aspects Part 3
Feb 29, 2024
2.4. The Influence of Physical Exercise on Hormonal Activity
In recent years, it has also been demonstrated that PE slows the development of neurodegenerative diseases from a hormonal point of view.
In modern society, more and more people are paying attention to the importance of health. Among them, physical health and mental health are equally important. And PE (physical exercise) is a very effective way to maintain and improve physical health. As for memory, PE also has a good impact.
After research, PE can improve people's cardiopulmonary function and metabolic rate, immunity, bone strength, etc. These are very beneficial to the human body's health. And these benefits can have a positive impact on a person's body in three to five years or even a lifetime.
PE can also improve people's mental state, which is beneficial to improving people's memory. For example, exercise can reduce people's stress and tension and make people more relaxed; exercise can promote blood circulation in the brain, thereby improving people's thinking and memory abilities. The improvement of memory can also further enhance people's self-confidence and enthusiasm.
In addition, PE can also improve people's social skills, thereby helping people communicate better with others. This is conducive to improving people's social skills and positive attitudes and promoting communication and mutual support between people.
In short, PE is a very important way to maintain good health. As for memory, PE can also have a good impact. Therefore, we should pay great attention to PE exercise to continuously improve our physical and mental health. It can be seen that we need to improve memory, and Cistanche deserticola can significantly improve memory, because Cistanche deserticola can also regulate the balance of neurotransmitters, such as increasing the levels of acetylcholine and growth factors. These substances are very important for memory and learning. In addition, Cistanche deserticola can also improve blood flow and promote oxygen delivery, which can ensure that the brain receives sufficient nutrients and energy, thereby improving brain vitality and endurance.
Click know supplements to boost memory
One of the main functions of the hippocampus consists of the inhibition and adaptive control of the hypothalamic–pituitary–adrenal axis (HPA) as a stress response [48]. Physiologically, the hippocampus contains many steroid receptors, divided into mineralocorticoid receptors (MR) and glucocorticoid (GR) [49].
It has been demonstrated that a physiological reduction in the number of steroid receptors in different areas of the hippocampus occurs with age [50] and that the HPA tends to free itself from the inhibitory control exerted by the higher centers.
Holsboer et al. developed a high-sensitivity test based on the combination of dexamethasone-suppression/corticotropin-releasing hormone stimulation (DEX/CRH test) to study the function of the HPA system.
The test results showed that basal cortisol concentration was significantly higher in AD patients than in healthy subjects and that the minimum drug concentration to which the patient reacts to cortisol was significantly higher in healthy subjects than in the AD patient group. In addition, AD patients released significantly less adrenocorticotropic hormone (ACTH) and cortisol after further CRH stimulation than the control group.
These results confirm that the regulation of the HPA system is impaired in AD. The impairment of the HPA axis and the corresponding increase in basal cortisol may be attributed to advancing age and the process of hippocampal destruction, which is typical of neurodegenerative diseases [51]. Lanfranco et al. demonstrated that PE also represents a powerful physiological stimulus on the HPA axis [52].
To understand the brain activation in response to PE, a comprehensive analysis was performed on rats after 90 min of treadmill running [53]. The results demonstrated hypersecretion of CRH, arginine-vasopressin hormone and ACTH, which conduce to an increase in basal adrenal cortisol secretion. Two major factors modulate the HPA axis response to resistance exercise: intensity and duration [54].
The minimum exercise intensity required to produce a cortisol response from the HPA axis is 60% of maximum oxygen consumption (VO2max); for exercise above 60% VO2max, plasma cortisol concentrations increase linearly with exercise intensity [55]. Below this intensity threshold (<60% VO2max), ACTH and cortisol concentrations may increase only if 90 minutes of exercise with at least 40% VO2max is maintained [56].
When PE is performed, a high response of hormones such as ACTH and cortisol occurs to mitigate the enormous metabolic demand essential to the body to complete the exercise itself [57].
Indeed, cortisol remodels muscle fibers by inhibiting the synthesis of new proteins and stimulating the degradation of the proteins through the ubiquitin pathway; moreover, cortisol affects neuromuscular function through various rapid and short-term mechanisms, such as the regulation of Ca2+ channels [58].
Moreover, Klaperski et al. showed that continuous, intense PE led to reduced stress reactivity and improved recovery from neuropsychological stress compared with physically inactive subjects [59]. Finally, adaptation to exercise induced a decreased peripheral tissue sensitivity to GCs that are supposed to protect the body from the severe metabolic and immune consequences of increased cortisol levels [60].
In conclusion, can determine transcriptional and translational changes at the cellular level, and it also induces a tissue biological stimulus at the CSN level and regulates the hormonal axes involving the brain. It therefore produces a cascade of positive biological and metabolic effects, both in terms of neuroplasticity and in terms of neuroprotection; for these reasons, it can be considered a real drug, devoid of any side effects for the CSN.
3. Physical Exercise-Related Clinical and Rehabilitative Effects in Neurodegenerative Diseases
At this point, it becomes essential to understand how the neurobiological effects of PE translate to a clinical level. Translating the perspective from the cell to the body and its function, from the particular to the general, is the indispensable premise for evaluating the effectiveness of PE as an opportunity for treatment and rehabilitation in the management of the most important neurodegenerative diseases that cause cognitive impairment (Figure 1).
3.1. The Role of Physical Exercise in Alzheimer's Disease (AD)
AD is certainly the most widespread and disabling neurodegenerative disease. AD is a neurodegenerative disease characterized by neuronal and synaptic changes in the cerebral cortex and in some subcortical regions, which cause the deterioration of cognitive and psychobehavioral functions [61]. The epidemiological data available over the last 10 years have shown that PE can slow down the progression of neurodegenerative diseases [62].
Aerobic PE increases cardiac output, and consequently, cerebral blood flow. This mechanism also involves an increase in angiogenesis, neurogenesis, synaptogenesis, and the synthesis of neurotransmitters, which in turn improve memory and cognitive functions [63].
Over the years, the correlation between aerobic PE and the improvement of cognitive function in subjects with AD has gained more and more evidence [64,65]. The effects of moderate physical activity on higher brain functions were first highlighted by observing how simple walking if carried out regularly, leads AD patients to improve their cognitive abilities, a result which is quantifiable by using the Mini-Mental State Examination (MMSE) [66].
Furthermore, according to a very large sample study conducted by Norton et al. [67], a percentage equal to 12.7% of AD cases worldwide and 20.3% of AD cases in Europe in 2010 were attributed to physical inactivity.
Additionally, the findings of a previous study published by Larson et al. were in line with these data: an analysis was conducted on a sample of 1740 individuals over the age of 65; all were subjected to a regular session of PE carried out for 2 years (15 min/session of walking, cycling, swimming, aerobics, rhythmic gymnastics, water aerobics, strength training, stretching or other activities).
For those who exercised three or more times per week, the incidence of dementia was found to be 13.0 per 1000 person-years; on the other hand, for those who exercised less than three times a week, the same incidence rose to 19.7 per 1000 person-years. As reported above, PE improves the cerebral vascular reserve and neuronal plasticity; in a study published by Larson et al., it was demonstrated that forty minutes of PE (ergocycle, treadmill, and stair-climbing) four times a week for 12 weeks could increase the cerebral blood flow in the hippocampal dentate gyrus, which can improve neurogenesis [68] and consequently can keep cognitive functions intact longer. All of this evidence confirms the importance of PE as a primary prevention tool.
Additionally, PE does not only work as a mechanism for the prevention of neurodegenerative diseases, but its contribution even in patients with moderate and advanced AD is now known. Indeed, in 2007 Rolland et al. demonstrated some of the positive effects of PE in patients with moderate AD. Two years of regular activity in these patients determined improvements in walking time endurance, reduction of depression, incontinence minimization, increase in activities of daily living (ADL), and, more generally, improvements in all the symptoms typical of this disease [69].
Even more surprising are the results of a study conducted by Venturelli et al. on a group of patients over the age of 65 with a diagnosis of advanced AD who underwent, with the help of their caregivers, a 24-week walking program for at least 30 min per day. Through assessment scales such as the Barthel index, MMSE, the Performance Oriented Mobility Assessment (POMA) index, and constant oxygen saturation during walking (SpO2 > 85%), it was seen that exercise can slow down, even if for short periods, the progression of cognitive impairment and can improve performance of ADL [70].
So, PE could also now be considered a rehabilitative opportunity since it improves the abilities of AD patients. Considering the absence of specific drugs to contrast AD, it seems to be very important to establish the dose–response effects of physical activity on the cognition of these patients, and consequently, to find the combinations of frequency, intensity, time, and type of PE most useful to optimize the results of this therapeutic intervention.
Although this intent is difficult to pursue, a recent meta-analysis [71] showed that, using MMSE as an evaluation scale, moderate intensity of aerobic exercise seems to be the most effective intervention, if it is conducted at least one hour a week and for a duration range from 12 to 24 weeks.
Moreover, the best cognitive improvement seems to be achieved with moderate intensity and frequency of physical activity: interventions conducted for up to 2 h had greater results than those conducted for more than 2 h per week; similarly, interventions conducted less than three times per week showed greater effect on improving cognition of AD patients compared to those conducted more than three times per week. Nevertheless, a threshold remains to be settled, since larger samples and longer follow-up are needed [72].
3.2. The Role of Physical Exercise in Parkinson's Disease (PD)
Continuing the examination of the main neurodegenerative diseases that cause cognitive impairment, it is certainly necessary to pay attention to Parkinson's disease as well. PD is a progressive neurodegenerative disease and is the second most common after AD, characterized by tremor, rigidity, bradykinesia, and postural instability. Its diagnosis is clinical even if a histopathological evaluation is necessary to identify α-synuclein contained in Lewy bodies or Lewy neurites [73]. PD etiology has not yet been clarified, but it seems to have a link to both genetic and environmental factors.
The main distinctive morphological change in the PD brain is observed in the transverse sections of the brainstem, where almost all cases present with loss of the darkly pigmented area in the substantia nigra pars compacta (SNpc) and locus coeruleus. From a clinical point of view, alongside the aforementioned pathognomonic motor deficits, people with PD can exhibit different cognitive conditions, from normal cognition, through to early, mild subjective and objective decline, to mild, moderate, and even severe PD dementia [74]. Severe dementia has a prevalence of 25–30% in PD patients and affects many cognitive functions, in particular, executive, attentional, and visuospatial domains, but also memory [75].
In this context, PE seems to also be a primary prevention tool for PD. In a study based on a sample of over 200,000 participants, people who practiced high levels of physical activity from ages 15–39 years were less exposed to be diagnosed with PD later in life [76]. In another epidemiological study, Thacker et al. analyzed a cohort of about 143,000 individuals and found that people who practiced moderate to vigorous physical activity, such as bicycling, aerobics, or tennis, had the lowest risk of PD during ten years of follow-up [77].
More specifically, PE seems to reduce the risk of developing cognitive impairment and PD, with a strong level of evidence for it being a protective factor for the latter [78]. However, PE is above all an opportunity for care in patients already suffering from PD. A comprehensive and recent review on the benefits of exercise training for PD patients highlighted the effects of different types of exercise on motor and cognitive dysfunctions: aerobic training, especially cycling, improves gait and cognitive function independently, but it also improves the motor learning ability, which translates into an improvement in motor functions applied to the gait [79].
Even more complex physical activities, such as dance, have proven effective not only in improving motor functions but also in implementing executive functions, assessable with the Frontal Assessment Battery at the bedside and Mental Rotation Tasks [80,81]. Additionally, Tai Chi, which is composed of dance-like movements that are linked together in a complex sequence, provides benefits for psychological well-being and cognitive function [82].
Similarly, yoga, which is a sporting practice that includes postures and exercises of breathing and meditation, improves balance, and mental and emotional health [83]. Moreover, PE is traditionally a pillar of rehabilitation treatments when it takes on the contours of therapeutic exercise. Therapeutic exercise, when organized in series with methodical exercises within programs aimed at specific rehabilitation objectives, can stimulate neuroplasticity at the level of the frontal lobe, counteracting cognitive impairment [84].
In particular, the exercises incorporating goal-based motor-skill learning improve motor-skill performance in PD through cognitive engagement. The cognitive benefits of therapeutic exercise translate into general improvements in autonomy in PD patients. The overall functionality, measured with scales such as ADL [85] and Barthel Index [86], improves significantly; this attests to the actual ability of the exercise to rehabilitate these patients, that is, to give them back their skills in carrying out the fundamental activities of their daily life.
The reduction of cognitive disabilities resulting from PD leads to an improvement in the quality of life [87]. A new frontier of neurorehabilitation deserves a special mention: virtual reality. Virtual reality plans to insert traditional exercise within virtual environments in which it is possible to exercise and monitor motor and cognitive functions in an easier and more precise way [88].
In PD patients, this type of sensorineural stimulation improves motor functions in terms of balance and gait, but above all increases executive functions [89]. In particular, virtual reality makes the training more complete, since it leads patients to simultaneously exercise multiple cognitive processes, linking them in sequences aimed at achieving specific goals, including those related to movement.
More specifically, attention activation, information acquiring and processing, movement planning, and sensory integration are contextually inserted into virtual contexts that require that they be applied to the daily activities of patients, to increase personal autonomy [90]. Additionally, PE can also limit the side effects such as wearing off and dyskinesia induced by anti-PD therapeutics, improving and prolonging the therapies' effectiveness [91]. Moreover, physical activity reduces the risk of other geriatric diseases such as diabetes, hypertension, and cardiovascular disease, which may also contribute to PD pathogenesis [92]. In summary, PE is now considered to be a complementary strategy to PD medications.
4. Conclusions
PE is an amazing health tool for the human brain, representing an opportunity for treatment and rehabilitation in patients suffering from cognitive impairment caused by neurodegenerative diseases. As described in this article, there is already evidence of how PE acts positively at the neuroendocrine and biochemical level, and which beneficial clinical implications derive from it.
Nevertheless, it is desired that new studies investigate the functional mechanisms of physical exercise at the brain level, revealing the fascinating aspects that remain unknown but could allow us to implement its therapeutic potential.
Author Contributions: Conceptualization, G.F., L.C. and M.M.; methodology, P.L., G.F., M.R., and L.C.; software, G.P.; formal analysis, P.L., and G.P.; investigation, G.F., M.V.R.; resources, M.V.R., A.C., G.M.; data collection, G.F., G.P., M.R.; writing original draft preparation, G.F., G.P., M.V.R., A.C., G.M., and M.M. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: The datasets used and/or analyzed during the current study will be made available upon reasonable request to the corresponding author, L.C.
Acknowledgments: We would like to thank Alessandra Zonno for her technical assistance.
Conflicts of Interest: The authors declare no conflict of interest.
References
1. Heemels, M.T. Neurodegenerative diseases. Nature 2016, 539, 179. [CrossRef] [PubMed]
2. Radi, E.; Formichi, P.; Battisti, C.; Federico, A. Apoptosis and oxidative stress in neurodegenerative diseases. J. Alzheimers Dis. 2014, 42 (Suppl. 3), S125–S152. [CrossRef]
3. Ferri, C.P.; Prince, M.; Brayne, C.; Brodaty, H.; Fratiglioni, L.; Ganguli, M.; Hall, K.; Hasegawa, K.; Hendrie, H.; Huang, Y.; et al. Global prevalence of dementia: A Delphi consensus study. Lancet 2005, 366, 2112–2117. [CrossRef]
4. Jong-wook, L. Global health improvement, and WHO: Shaping the future. Lancet 2003, 362, 2083–2088. [CrossRef]
5. Dembitsky, V.M.; Dzhemileva, L.; Gloriozova, T.; D'yakonov, V. Natural and synthetic drugs used for the treatment of the dementia. Biochem. Biophys. Res. Commun. 2020, 524, 772–783. [CrossRef]
6. Reddy, P.H. Lifestyle and Risk Factors of Dementia in Rural West Texas. J. Alzheimers Dis. 2019, 72, S1–S10. [CrossRef] [PubMed]
7. Marques-Aleixo, I.; Beleza, J.; Sampaio, A.; Stevanovi´c, J.; Coxito, P.; Gonçalves, I.; Ascensão, A.; Magalhães, J. Preventive and Therapeutic Potential of Physical Exercise in Neurodegenerative Diseases. Antioxid. Redox Signal. 2021, 34, 674–693. [CrossRef] [PubMed]
8. Raichlen, D.A.; Gordon, A.D. Relationship between exercise capacity and brain size in mammals. PLoS ONE 2011, 6, e20601. [CrossRef] [PubMed]
9. Cassilhas, R.C.; Tufik, S.; de Mello, M.T. Physical exercise, neuroplasticity, spatial learning and memory. Cell. Mol. Life Sci. 2016, 73, 975–983. [CrossRef] [PubMed]
10. Kirk-Sanchez, N.J.; McGough, E.L. Physical exercise and cognitive performance in the elderly: Current perspectives. Clin. Interv. Aging 2014, 9, 51–62. [CrossRef]
For more information:1950477648nn@gmail.com
