The Effect Of Physical Exercise On Cognitive Impairment in Neurodegenerative Disease: From Pathophysiology To Clinical And Rehabilitative Aspects Part 1

Abstract: Neurodegenerative diseases are a group of pathologies that cause severe disability due to motor and cognitive limitations. In particular, cognitive impairment is a growing health and socioeconomic problem that is still difficult to deal with today. 

Neurodegenerative diseases refer to a class of diseases characterized by degeneration of the nervous system. These diseases can severely affect a patient's body functions, including memory. However, even having a neurodegenerative disease does not necessarily mean that memory is irreversibly damaged.

There are many things we can do to help relieve the symptoms of memory loss. For example, we can promote the health of brain nerve cells and slow down the progression of neurodegenerative diseases by maintaining a positive attitude towards life, strengthening social connections, participating in cultural and artistic activities, and persisting in sports.

Additionally, one treatment that is widely seen as effective is cognitive training, such as mind games and cognitive exercises that specifically target cognitive abilities, which have been shown to help improve memory and thinking skills, especially in people with neurodegenerative disease. disease patients.

Finally, we must also pay attention to our physical and mental health and avoid unhealthy lifestyle habits such as excessive stress, insomnia, lack of exercise, poor diet, etc. These factors will cause harm to our brain function.

We should believe that with the joint action of a positive attitude towards life, scientific treatment methods, and good health habits, even if we suffer from neurodegenerative diseases, we can still maintain a positive attitude towards life, overcome various difficulties, and have a healthy body and soul, not letting disease become a stumbling block that affects our lives. It can be seen that we need to improve memory, and Cistanche deserticola can significantly improve memory because Cistanche deserticola is a traditional Chinese medicinal material that has many unique effects, one of which is to improve memory. The efficacy of Cistanche deserticola comes from the multiple active ingredients it contains, including tannic acid, polysaccharides, flavonoid glycosides, etc. These ingredients can promote brain health through a variety of pathways.

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As there are no pharmacologically effective treatments for cognitive deficits, scientific interest is growing regarding the possible impacts of healthy lifestyles on them. In this context, physical activity is gaining more and more evidence as a primary prevention intervention, a nonpharmacological therapy, and a rehabilitation tool for improving cognitive functions in neurodegenerative diseases. 

In this descriptive overview, we highlight the neurobiological effects of physical exercise, which can promote neuroplasticity and neuroprotection by acting at the cytokine and hormonal level, and the consequent positive clinical effects on patients suffering from cognitive impairment.

Keywords: physical activity; exercise; rehabilitation; Alzheimer's disease; Parkinson's disease.

1. Introduction
Neurodegenerative diseases are a group of hereditary disorders of the central nervous system, that cause slow, progressive damage to specific neuron populations and their connections [1]. 

They can cause severe clinical consequences, such as motor and cognitive disability, and care dependency [2]. In particular, the impairment of cognitive abilities is a growing health and socioeconomic problem. 

Dementia and mild cognitive impairment (MCI) cases are estimated to increase in Europe from 7.7 million in 2001 to 15.9 million in 2040 [3]. According to the estimates provided by the Global Burden of Disease in 2003, dementia contributed to 11.2% of years lived with disability in people aged 60 and over, more than strokes, musculoskeletal disorders, cardiovascular disease, and all forms of cancer [4]. 

Costs of dementia are forecasted to rise in the whole European continent by about 43% between 2008 and 2030, to over EUR 250 billion. Therefore, the research regarding this disease represents a real challenge for physicians and rehabilitators. 

Many treatment strategies have been tested, using both drugs and rehabilitation techniques [5]. Furthermore, great interest has been placed on the importance of lifestyles both in the management and in the prevention of cognitive limitations deriving from neurodegenerative diseases [6]. 

Among the life habits, the possible role of physical activity seems increasingly interesting. There has long been discussion regarding the positive effects of physical exercise (PE) on brain activity [7]. Raichlen et al. reported a positive correlation between the size of the human brain and endurance-exercise capacity, suggesting a coevolution between locomotion and cognition in humans [8]. 

However, PE has only recently begun to receive the attention of the international scientific community, especially around its possible effects on cognitive functions, spatial learning, and memory, as a nondrug method of maintaining brain health and treating neurodegenerative and psychiatric conditions [9]. 

The beneficial effects of aerobic and resistance exercises in adult and geriatric populations have been demonstrated [10], and in the same way, rehabilitative therapeutic exercise seems to be an effective instrument to try to slow down the unavoidable progression of cognitive impairment in pathologies such as dementia [11]. 

So, PE provides a nonpharmacological approach to slowing age-related decline and reducing disease-related cognitive impairment in older adults through the reduction of risk factors and its neuroprotective capacity. 

Nevertheless, the biochemical and molecular bases underlying the neuroplasticity mechanisms are still partly unclear, as are the processes that translate the effects of PE into neurological and clinical benefits [12]. 

The aim of this literature descriptive overview is to investigate whether PE has a clinically positive and rehabilitation-improving effect on cognitive impairment related to neurodegenerative diseases and to understand more deeply the neurobiological mechanisms that explain these processes.

2. Physical Exercise-Related Neurobiological Processes in Neurodegenerative Disease

The maintenance of cognitive function lies in the processes of neuroplasticity and neuroprotection (Figure 1).

Neuroplasticity is the ability of the brain to alter functional and structural properties to respond to changing demands, and it results in learning and acquiring skills [13]. It is well known that PE facilitates neuroplasticity of certain brain regions, and as a result, it improves cognitive functions [14]. 

Farmer et al. demonstrated that hippocampal neurons grow and develop from a single population of stem cells in response to exercise [15]. New neurons are more flexible in making connections than mature ones, allowing for healthy learning, a good memory, and mood regulation [16]. 

Moreover, to make many brain activities work properly, the hippocampus plays a role through the secretion of some stimulating factors such as brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF), and insulin-like growth factor (IGF-1), which together with synapsins and synaptophysins induce downregulation of oxidative stress and apoptotic functions [17]. Increased release of protective neurotrophins is associated with PE in animal and human studies [18].

2.1. Neurotrophin Modulation Induced by Physical Exercise

BDNF belongs to a family of small, secreted proteins that also include nerve growth factor, neurotrophin 3, and neurotrophin 4. It acts as an antiapoptotic and antioxidant agent and tends to suppress all the autophagy processes induced by microglia and proinflammatory cytokines [19]. 

BDNF stands out among all neurotrophins due to its high expression levels in the brain and its potent effects at synapses [20]. Furthermore, Churchill et al. in 2002 indicated that BDNF neurotrophin is involved in information storage processes in long-term memory and learning [21]. 

Physiologically, after an ischemic insult, the microglia are activated and act with proinflammatory activity, leading to an increase in free oxidative radicals (ROS) to which neuronal cells try to respond by consuming ATP and inevitably dying; therefore, increasing the levels of BDNF through PE could reduce the impact of these events [21]. PE increases the expression of BDNF but also of IGF-1, which interacts with BDNF to mediate exercise-induced cognitive gains [22–24]. 

Mattson et al. suggested that, since endurance exercise increases BDNF expression in the brain, the improvement in exercise capacity may positively enforce brain growth, especially in the hippocampus [25]. So, exercise training is known to enhance the neuronal functions of the amygdala and hippocampus, since it seems to increase the levels of BDNF/TrkB signaling molecules [26]. 

Fahimi et al. reported that around four weeks of treadmill and running wheel exercises in mice brought about many changes such as significant increases in BDNF-mRNA and protein levels, significantly increased synaptic load in dentate gyrus, changes in the morphology of astrocytes and orientation of astrocytic projections toward dentate gyrus cells [27]. 

Zsuga et al. suggested also that BDNF modulates neuronal dopamine content and its release, which are essential for neuronal plasticity, neuronal survival, learning, and memory [28]. So, BDNF concentration's increase in blood after PE seems to be a preventive factor for cognitive impairment. Like BDNF, IGF-1 also promotes neuronal growth, survival, and differentiation. 

Its blood concentration seems to increase in older adults after 6 months of moderate-to-high levels of resistance exercise [29]. Although the specific molecular actions of IGF-1 that contribute to improved cognitive performance in aged animals remain unknown, there is new evidence that synaptic morphology and function are regulated by IGF-1. Shi et al. quantified total synaptic profiles as well as synaptic profiles in multiple spine bouton (MSB) complexes in the CA1 region of the hippocampus and determined the postsynaptic density (PSD) length. 

The results indicated a decrease in total synapses between middle and old age, but IGF-1 infusion in old animals increased PSD length and the number of MSB synapses. These changes appear to be morphological correlates of increased synaptic efficacy and suggest that IGF-1 levels influence synaptic function in the CA1 region of the hippocampus [30]. 

These findings could indicate that circulating IGF-1 is essential for protecting normal brain function. Moreover, Trejo et al. demonstrated that behavioral and synaptic deficits were improved in IGF-1-deficient mice by prolonged systemic administration of IGF-1, which normalized the density of glutamatergic buttons in the hippocampus. These results indicate that circulating IGF-1 also influences mature brain function, i.e., learning and synaptic plasticity, through its trophic effects on central glutamate synapses [31]. 

Therefore, raising the levels of circulating IGF-1 through PE is important not only to prevent the appearance of cognitive impairment but also to improve cognitive performance in those affected.

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