The Relationship Between Exercise,Cathepsin B,and Cognitive Functions: Systematic Review

Abstract

Exercise has been shown repeatedly to improve cognitive functions. Many investigators have reported that peripheral signal molecules play an important role in regulating exercise-induced cognitive improvement. In this review we aimed to evaluate and clarify the literature to date that has focused on the relationship between Cathepsin B, cognitive functions, and exercise. We conducted a systematic review of the following databases from their inception until 10 April 2022: Pubmed, Web of Science, Scopus, Cochrane Library, Physiotherapy Evidence Database. The search strategy was comprised of (“cathepsin b”) AND (exercise OR “physical activity”) AND (cognit*). We followed three different quality appraisal tools to ensure the quality of the included studies. Eight studies assessing the effects of exercise on peripheral Cathepsin B levels and cognitive outcomes were included. Half of these studies indicated that exercise increased peripheral Cathepsin B levels and improved cognitive function. Further carefully designed studies focusing on the effects of exercise on peripheral Cathepsin B levels and cognitive performance are needed to better comprehend the underlying mechanisms of these relationships.

Keywords

physiotherapy exercise effects cognitive benefits to exercise cortical changes brain health

Introduction

The benefits of exercise on health status are well known (Tipton, 2014). In recent years, a large body of evidence has supported improvements from exercise on brain health and cognitive function (Kempermann et al., 2000; Cabral et al., 2019; Ma et al., 2017; Rodriguez-Ayllon et al., 2019). Neuroscience researchers have also demonstrated preventive and therapeutic effects of exercise on cognitive performance across age groups, from childhood to the elderly, for either better health or relief from disease conditions (Donnelly et al., 2016; Falck et al., 2019; Neudecker et al., 2019; Young et al., 2015). Considering the added societal pressures from aging and disease now trending in the world’s population (GBD 2019 Collaborators, 2021), comprehending the underlying mechanisms of the relationship between exercise and cognition is an urgent modern need. Besides the direct effect of exercise on angiogenesis, synaptogenesis, and neurogenesis within the brain, evidence is accumulating that peripheral factors mediate the brain’s response to exercise (Pedersen, 2019a, 2019b; Townsend et al., 2021).

Exercise-induced peripheral humoral factors released from skeletal muscles and organs are collectively termed “exerkines” (Safdar et al., 2016). Exerkines are considered one of the potential mechanisms mediating the exercise effect on the brain (Lee et al., 2019). Myokines are muscle-derived exerkines produced and released by exercising muscles, and these factors mediate the exercise effect on several tissues, including the brain (Pedersen, 2019a). Cathepsin B is one of the several myokines that has been found to be secreted in response to exercise (Moon et al., 2016).

Cathepsins are proteases that are responsible for protein degradation. The word cathepsin is derived from ancient Greek words, “kata” (down) and “hepsein” (boil), in compliance with its place in the vital cycle (Willstatter & Bamann, 1928). There are 15 human cathepsins expressed extensively in almost all cells, but they differ in their expression levels (Cocchiaro et al., 2017; Tamhane et al., 2014).

Cathepsin B (CTSB) is the first lysosomal cysteine proteinase purified to homogeneity and belonging to the group of proteases in the endosomal-lysosomal system (Sloane, 1990) with a calculated molecular weight of 30 kDa (Schmitz et al., 2019). CTSB was found to be capable of crossing the blood-brain barrier (Moon et al., 2016), and it has been shown to have a variety of roles, including tumor proliferation (Aggarwal & Sloane, 2020), angiogenesis (Kruszewski et al., 2004), immune responsivity (Ha et al., 2008; Zhang et al., 2019), skeletal myoblast differentiation (Jane et al., 2002), neurogenesis (Moon et al., 2016; Nakanishi, 2020a; 2020b), hormone activation, and bone turnover (Mort & Buttle, 1997) through its different subcellular localizations of isoforms.

Research on the role of CTSB in brain function has produced inconsistent findings. It has been reported that CTSB has anti-amyloidogenic properties (Mueller-Steiner et al., 2006) and a neuroprotective function (Bendiske & Bahr, 2003) in the brain. However, CTSB has also been associated with cell death and inflammation processes that cause neurodegeneration (Hook et al., 2020). Increased plasma CTSB levels have been demonstrated in Alzheimer’s Disease when these patients were compared to healthy controls (Sundelöf et al., 2010; Morena et al., 2017).

Recent experimental researchers proposed that Cathepsin B is increased in both skeletal muscle and peripheral circulation following muscle contractile activity, which in turn can affect cognitive function (Moon et al., 2016, Gokce et al., 2021). Although a growing number of investigators have sought to understand the effect of exercise on cognitive functions, focusing on myokines (Kim et al., 2019; Piepmeier & Etnier, 2015; Vaynman et al., 2004), no researcher has systematically addressed CTSB. Since a synthesis of recent evidence may assist in elucidating the link between exercise, Cathepsin B, and cognitive function, we aimed to review research on the effects of exercise on CTSB levels in healthy populations by focusing on cognitive functions.

Method

This review was registered with The International Prospective Register of Systematic Reviews (PROSPERO) database (Registration no: CRD42022302294).

Search Strategy

We conducted this systematic review by following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement (Moher et al., 2009). Two authors of this study independently searched five electronic databases (Pubmed, Web of Science, Scopus, Cochrane Library, Physiotherapy Evidence Database (PEDro)) from their inception until 10 April 2022. To ensure high sensitivity of our literature search, we performed a title, abstract, and keyword search by applying the following search strings, individually adjusted for each database: (“cathepsin b”) AND (exercise OR “physical activity”) AND (cognit*). There were no restrictions on the dates of studies or the language used.

Selection Criteria

We included studies with human trials that included at least one exercise session and that assessed peripheral CTSB levels and cognitive function. All included studies had to be published in peer-reviewed journals and were performed in healthy populations. Review articles were excluded.

Data Extraction and Methodological Quality Assessment

Two reviewers independently evaluated the risk of bias for each eligible study. A third reviewer resolved disagreements concerning inclusion when required. We also evaluated the methodological quality of the research designs in the included studies (See Supplementary Materials). Randomized-controlled studies were evaluated by the PEDro scale, which is widely accepted as a reliable and valid quality assessment scale for this purpose (Maher et al., 2003; Elkins et al., 2013). The scale consists of 11 items comprising themes of external validity (item 1), internal validity (items two–9), and statistical reporting (items 10–11). Each criterion is rated yes or no (1 or 0), based on whether the criterion was clearly satisfied in the study, and the first item is not rated. The obtained quality score is then classified into excellent (9–10), good (6–8), fair (4–5), poor (0–3).

Cross-sectional studies were evaluated by The Joanna Briggs Institute (JBI) Critical Appraisal Checklist. This scale consists of eight items based on the study’s design, conduct, and analysis. Answers are “Yes,” “No,” “Unclear,” or “Not Applicable.” The JBI allows authors to “include” or “exclude” studies based on the overall rating. The criterion we used for this review was to exclude the study if the quality rating was had ≥3 and classified as “no” or “unclear” (Moola et al., 2020).

Studies without control groups were evaluated by The National Institutes of Health (NIH) quality assessment tool for before-after (Pre-Post) studies with no control group. The scale consists of 12 items, and the answers are “Yes,” “No,” and “Cannot Determine/Not Applicable/Not Reported.” The obtained quality score is then classified into good, fair, or poor (NIH,2014).

Results

Study Design and Participant Characteristics

Our initial database screening identified 71 prospective studies. After removing duplicates (n = 35) and after title and abstract screening, only eight studies met our eligibility criteria (19 were reviews, three were unfinished, one was a book chapter, one was editorial material, one contained non-relevant content, one included no cognitive assessment, and two were animal studies). A comprehensive flow chart of the search process is reported in Figure 1.

Figure 1.

Flow Diagram Describing Selection of Relevant Papers in the Review.

Characteristics of all included studies, including their participant samples, study designs, exercise interventions, cognitive outcomes, CTSB sources, and quality scores are reported in Table 1. All eight included studies were published between 2016–2022 and had been conducted in six countries (Canada: 2, Poland:1, Spain:1, Turkey:1, UK: 1, USA: 2). Six studies used experimental designs (Gaitán et al., 2021; Gourgouvelis et al., 2018; Micielska et al., 2021; Moon et al., 2016; Nicolini et al., 2019 Malcolm et al., 2022), one study had a cross-sectional design (De la Rosa et al., 2019), and one study had both cross-sectional and experimental sections (Gokce et al., 2021). The sample size ranged from 18 to 68 participants. There were a total of 298 participants across all the included studies, and the majority of the participants were males (n = 171). Two studies recruited only males (De la Rosa et al., 2019; Nicolini et al., 2019), and one study recruited only females (Micielska et al., 2021). The average age of participants ranged between 18 and 68 years.

Table 1.

Study Characteristics.

1st Author	Sample	Study Design	Intervention	Cognitive Outcomes	CTSB Resource	Results
Moon et al. (2016)	n = 43 (19 male) Age: 19–34 y.o	USA Two groups (C, E) RCT	4 months of treadmill exercise, 3 times per week, moderate to intense intensity	CFDR	Plasma*	E: CTSB ∆CTSB positively correlated with ∆CFDR
Gourgouvelis et al. (2018)	n = 22 (10 male) Age: 21.10 ± 1.27	Canada, Two groups (C, E) RCT	8 weeks, twice per week. Moderate to vigorous intensity aerobic exercise in combination with resistance activites.	- Recognition memory - Visual memory - Visual spatial recognition - Visual discrimination and attention	Plasma**	No change both CTSB and cognitive functions
De la Rosa. (2019)	n = 68 (male) Age: 17–68 y.o	Spain, Four groups (YSG, YTG MSG, MTG) CSS	YTG: Regular exercise for 7 years MTG: Regular exercise for 35 ± 15 years	-Attention -Psychomotor speed -EF -Spatial WM -Rapid visual information processing -Paired associate learning -FCSRT	Plasma*	CTSB↓ in MTG, YTG FCSRT ↑ in MTG
Nicolini et al. (2019)	n = 18 (male) Age: 23.1 ± 3.5	Canada, One group UT	6 weeks, 3 times per week. 17.5 minutes HIIT.	WM	Serum***	No change both CTSB and WM
Gaitan et al. (2021)	n = 23 (12 male) Age: 64.9	USA, Two groups (UPA, EPA) RCT	EPA: 26 weeks of supervised treadmill training, 3 times per week, moderate to vigorous.	-CVLT -Verbal fluency -Design fluency -Trail making -Sorting -Interference	Plasma*	EPA: CTSB ↑, ∆CTSB positively correlated with ∆CVLT total score
Gokce et al. (2021)	n = 54 (25 male) Age: 18–25 y.o	Turkey Three groups (F, S, C) CSS, UCT	-F, S: At least 5 years of regular sport activity -One bout of aerobic exercise, 40 minutes, moderate	-Visuospatial WM -Selective attention -Verbal fluency	Serum****	- Basal CTSB ↑ in F - ∆CTSB ↑ in F, S - F ↑ visuospatial WM, selective attention, verbal fluency -F, S ↑ visuospatial WM, selective attention,
Micielska et al. (2021)	n = 33 (female) Age: 39 ± 13	Poland, Two groups (C, E) RCT	E: 5 weeks, 3 times per week HICT C: twice HICT (baseline and the end)	-Spatial short-term memory -Response inhibition	Plasma*	E: CTSB ↑ ∆CTSB positively correlated with improved cognitive function
Malcolm et al., 2022	n = 37 (17 male)	UK, One group RCT	one session field hockey match	-EF -Attention	Plasma*	No change for CTSB Response time↓ WM↓

Note: C: Control group; CFDR: Complex figure drawing recall test; CSS: Cross-sectional study; CTSB: Cathepsin B; CVLT: California verbal learning test; E: Exercise group; EF: Executive functions; EPA: Enhanced physical activity; F: Fencers; FCSRT: Free and Cued Selective Reminding Test; FH: Field hockey; HICT: High intensity circuit training; HIIT: High intensity interval training; MSG: Middle-aged sedentary group, MTG: Middle-aged trained group; RCT: Randomized Controlled Trial; S: Swimmers; UPA: Usual physical activity; UT: Uncontrolled trial; y.o: Years old; YSG: Young sedentary group, YTG: Young trained group, WM: Working memory. Superscripts indicate the ELISA kit which is used to assess the sample.

*Abcam, Human Cathepsin B; ** BioLegend, San Diego, CA, USA; ***R&D Systems, Minneapolis, MN; **** MyBioSource Cathepsin B.

Quality Assessment

The quality of the included studies varied. Among randomized controlled studies, four had “good” and one study had “excellent” quality. One intervention study with no control group had a “fair” quality score. We also included the cross-sectional studies because the JBI assessment tool resulted in less than three ‘no’ or ‘unclear’ ratings. The most frequent risk of bias was in the process by which the participants were kept unaware of the study’s purpose. (See Appendix)

Exercise Characteristics

Five studies evaluated the effects of chronic exercise with training interventions that lasted from 5 weeks to 4 months, with sessions twice per week (Gourgouvelis et al., 2018) and three times per week (Moon et al., 2016; Micielska et al., 2021; Gaitan et al., 2021; Nicolini et al., 2019). The frequency of weekly exercise interventions was three times per week in four studies (Moon et al., 2016; Micielska et al., 2021; Nicolini et al., 2019) and twice per week in one study (Gourgouvelis et al., 2018). The included exercise dose varied from moderate to vigorous intensity. One study had no exercise intervention and assessed the effects of long-term sport participation activity (from 7 to 50 years) (De la Rosa et al., 2019). One study assessed both the effects of long-term exercise (from 5 to 10 years) and acute aerobic exercise (40 minutes, moderate intensity) performed by the same participants (Gokce et al., 2021). One study assessed an acute exercise effect (field hockey match) (Malcolm et al., 2022). In five studies, training was supervised by a qualified exercise professional (Gaitan et al., 2021; Gourgouvelis et al., 2018; Gokce et al., 2021; Micielska et al., 2021; Nicolini et al., 2019).

Blood Samples and Cognitive Outcomes

Six studies assessed CTSB in plasma (De la Rosa et al., 2019; Gaitan et al., 2021; Gourgouvelis et al., 2018; Malcolm et al., 2022; Micielska et al., 2021; Moon et al., 2016), whereas two studies assessed CTSB in serum (Gokce et al., 2021; Nicolini et al., 2019). Studies involving acute and chronic exercise interventions assessed CTSB levels twice - at baseline and at post-exercise. Four different commercially available enzyme-linked immunosorbent assays (ELISA) kits were used to determine the CTSB levels (See Table 1).

The included studies used a variety of cognitive performance measurement systems, including the Cambridge Neuropsychological Test Automated Battery (CANTAB) (De la Rosa et al., 2019; Gourgouvelis et al., 2018; Nicolini et al., 2019), a computerized battery, the Vienna Test System (Micielska et al., 2021), and batteries developed by the technicians of the studies (Gaitan et al., 2021; Gokce et al., 2021; Malcolm et al., 2022). One study did not explicitly describe the cognitive test battery (Moon et al., 2016). Executive functions, verbal fluency, attention, information processing were the main cognitive domains in the included studies. For more comprehensive details of the cognitive measurements, see Table 1.

Effects of Exercise on CTSB

As displayed in Table 1, four studies reported that exercise increased CTSB levels in peripheral circulation. Moon et al. (2016) showed that four months of treadmill exercise increased the plasma CTSB levels. Gaitan et al. (2021) showed that 26 weeks of treadmill exercise increased the plasma levels of CTSB in middle-aged adults. Micielska et al. (2021) demonstrated that five weeks of HICT increased the plasma CTSB levels in middle-aged women. Gokce et al. (2021) compared the long-term effects of open and closed-skill regular sport activity on CTSB and demonstrated that open-skill athletes had higher basal CTSB levels. They also assessed the acute exercise effect on CTSB and showed that CTSB levels were increased in open-skill athletes. One study showed long-term regular sport activity decreased the plasma CTSB levels. De la Rosa et al. (2019) demonstrated that long-term sport participation, including tennis, running, football, taekwondo in young adults, and rugby in middle-aged adults decreased the basal plasma CTSB levels. Three studies showed that CTSB levels did not change after chronic and acute exercise: Gourgouvelis et al. (2018) demonstrated that eight weeks of exercise did not change plasma CTSB levels in young adults, and Nicolini et al. (2019) demonstrated that 6 weeks of HIIT did not change serum CTSB levels in young males. Malcolm et al. (2022) demonstrated that acute field hockey match did not change plasma CTSB levels in young athletes.

Effects of Exercise on Cognitive Performance by Focusing CTSB

Six of the included studies reported cognitive improvement following exercise intervention or regular exercise training (see Table 1). Moon et al. (2016) showed that four months of treadmill exercise improved the hippocampus-dependent memory function, and memory function was correlated with changes in plasma CTSB levels. Gaitan et al. (2021) showed that 26 weeks of treadmill exercise improved verbal learning and memory function in middle-aged adults, and there was a positive correlation between plasma CTSB change and cognitive performance. Micielska et al. (2021) demonstrated that five weeks of HICT improved spatial short-term memory and response inhibition. Improvement of cognitive performance was accompanied by shifts in plasma CTSB levels. Gokce et al. (2021) demonstrated that long-term sport activity improved visuospatial working memory, attention, and verbal fluency. However, they did not perform correlational analyses between cognitive performance and serum CTSB levels. Malcolm et al. (2022) demonstrated that an acute field hockey match improved response time for a perception task but decreased working memory. There was a positive correlation between changes in CTSB levels and the change in accuracy on a visual search task. De la Rosa et al. (2019) demonstrated that long-term sport activity improved verbal and episodic memory, and there was a negative relationship between cognitive performance and plasma CTSB levels. Two studies reported no significant change in cognitive performance following exercise intervention, and there was also no significant change in peripheral CTSB levels (Gourgouvelis et al., 2018; Nicolini et al., 2019).

Discussion

In the present systematic review, we aimed to synthesize the evidence for the effects of exercise on peripheral CTSB levels by focusing on cognitive outcomes. Half of the studies included in this review supported the notion that exercise significantly increases peripheral CTSB levels and improves cognitive function. These results support previous literature that provided fundamental insights into how exercise improves brain health through exercise-induced increases in peripheral proteins and cognitive function.

Various myokines, such as BDNF, IGF-1, and IL-6 have been reported to mediate the role of exercise on cognitive functions via the cross-talk between muscle and brain (Kim et al., 2019). Our findings indicate that CTSB might be one of these myokines, suggesting that it acts as a peripheral signal, following muscle contraction in the muscle-brain endocrine loop. CTSB, which has been shown to pass through the blood-brain barrier in animal models (Moon et al., 2016), may reach the brain via peripheral circulation following muscle contraction and thereby improve neuronal tissue. Indeed, Moon et al. (2016) demonstrated that exercise increased CTSB levels in mouse and human plasma, and that plasma CTSB levels were positively correlated with fitness and memory, whereas CTSB-knockout mice did not show cognitive improvement following running exercise. From this standpoint, it is likely that exercise-induced cognitive improvement cannot be triggered without CTSB. Contrary to most findings in the included studies we reviewed, Sun et al. (2015) indicated that increased peripheral CTSB levels were associated with cognitive dysfunction. However, it should be kept in mind that these authors recruited an unhealthy population in the form of patients with Alzheimer’s Disease as opposed to the healthy populations of studies in our review.

CTSB plays a key role in modulating angiogenic processes (Noda et al., 2012), and exercise also induces angiogenesis (Kwak et al., 2018). It has been demonstrated that cerebral perfusion and cognitive performance are positively correlated (Wightman et al., 2015). Taken together, it is conceivable that CTSB may be an element of the relationship between exercise, angiogenesis, and cognitive performance. Considering that the relationship between CTSB and angiogenesis is demonstrated in pathological tissues, more data on the effect of CTSB on angiogenesis in healthy tissue are needed. We should also note that the human blood-brain barrier is structurally and functionally different from that of animal models, meaning that we cannot easily inferred that CTSB concentration is increased in the brain following a peripheral increase.

The effects of exercise on cognition and the regulation of peripheral signal responses depend on several factors, such as exercise type, intensity, frequency, and duration (Bartha et al., 2017; Sanders et al., 2019). Those factors may also determine how long exercise effects last following a training intervention (Colcombe & Kramer, 2003). For instance, BDNF, is one of the peripheral myokines that has been demonstrated to respond differently to different types of exercise. A meta-analysis demonstrated significant peripheral BDNF increases after strength exercise and combined aerobic/strength exercise, but not after aerobic exercise alone (Marinus et al., 2019). On the contrary, Dinoff et al. (2016) and Fleitas et al. (2022) proposed that aerobic exercise, but not resistance training, increased resting BDNF concentrations in peripheral blood. Others also demonstrated that cognitive responses to physical exercise vary with exercise types. Iuliano et al. (2015) suggested that endurance exercise has greater effects on general cognition than resistance exercise. A systematic review demonstrated that coordinative exercise is the most effective exercise type to improve cognitive function (Ludyga et al., 2020). Others have shown that varied exercise types, such as aerobic versus coordinative or resistance versus mixed exercise training, did not affect cognition or peripheral protein responses (Ansai et al., 2016; Ludyga et al., 2019; Ruiz-Gonzalez et al., 2021).

In the present review, investigators that showed a CTSB increase and cognitive improvement had their participants perform aerobic exercise and HICT (Moon et al., 2016; Gaitan et al., 2021; Gokce et al., 2021; Micielska et al., 2021). Studies in which CTSB and cognitive parameters did not change consisted of HIIT (Nicolini et al., 2019), and a combination of aerobic and resistance exercises (Gourgouvelis et al., 2018). Considering that field hockey uses both aerobic endurance and anaerobic power, this mixed type intervention study also failed to change CTSB levels and induced varied cognitive responses (Malcolm et al., 2022). Given the limited number of included studies and their mixed results, it is difficult to explain such variance among exercise types in the effects of exercise on CTSB and cognitive outcomes.

In addition to exercise type, exercise dose parameters are also important for the magnitude of effects on peripheral signals and cognitive performance. Dose parameters contain exercise intensity, exercise frequency, and intervention duration. Dose–response relationships also vary, depending on the exercise type (Gallardo-Gómez et al., 2022). Many investigators found that exercise-induced changes in peripheral signals and cognitive function were intensity-dependent and favored high-intensity exercise (Boyne et al., 2020; Jeon et al., 2017; Reycraft et al., 2020; Schmidt-Kassow et al., 2012; Loprinzi et al., 2022). However, other researchers showed that exercise increaseed peripheral signal levels and had beneficial effects on cognitive function, independently of its intensity (Ruscheweyh et al., 2011; Cassilhas et al., 2007).

In this review, CTSB was increased and cognitive improvement was moderate to vigorous with high intensity exercise (Moon et al., 2016; Gaitan et al., 2021; Micielska et al., 2021). In the acute intervention study, exercise intensity was moderate, and the CTSB increase was observed only in the athlete groups (Gokce et al., 2021). It is difficult to compare the effects of exercise intensity across studies, due to the small number of studies included in this review and the lack of research on low-intensity exercise. Further research involving different interventions will help to better understand the exercise intensity effect on CTSB response and cognitive performance.

The other potential factor that may be relevant to the exercise effect on peripheral signal response and cognitive performance might be the frequency and duration of exercise (Colcombe & Kramer, 2003; Forbes et al., 2015; Sanders et al., 2019; Schmolesky et al., 2013). Frequency is the number of times per week that an exercise is performed. In the present review, exercise frequency ranged from 2–3 times per week. The exercise frequency was three times per week in the intervention studies that showed an increase in baseline CTSB and cognitive performance levels. The investigators that did not report a shift for these assessments used a frequency of two and three exercise interventions per week. An implication of this finding from our review is the possibility that an exercise frequency of three times per week might be better for inducing a CTSB response and cognitive improvement. However, these findings are limited, due the small number of studies reviewed.

Exercise duration refers to the number of weeks of exercise an investigator used during the intervention period. In the present review, exercise durations ranged from 5-26 weeks. Considering that 5 weeks of exercise intervention increased the participant’ CTSB levels and cognitive performances but six or 8 weeks did not, it is not easy to discuss the effect of exercise duration. Additional studies are needed to explore which combination of exercise type, intensity, frequency, and duration may have an optimal effect on CTSB response and cognitive performance.

One other important factor related to the results of the peripheral myokine response to exercise may be pre-analytical variables such as the blood sampling procedure, blood processing, and blood storing that investigators used (Lombardi et al., 2017). In this review, three research teams performed plasma (Moon et al., 2016; Gaitan et al., 2021; Micielska et al., 2021), and one performed serum analysis (Gokce et al., 2021). No researchers reported the exact interval between the sampling and analysis. Future studies might consider the pre-analytical variables that potentially affect the CTSB measurement to permit a more reliable comparison.

Limitations and Future Directions

Although this is the first review focusing on the relationship between exercise, CTSB, and cognition, our findings must be considered in the context of several limitations. Few available studies was our main limitation. Further experimental research is needed for a more extensive comparison of different age groups, differences in the type, intensity, and duration of the exercise intervention, and differences in CTSB measurement samples such as serum, plasma, or tissue. A wider range of neuropsychological assessments might also bring important insight and a more complete understanding of the relationship between exercise, CTSB, and cognition.

Conclusion

An exercise effect on cognitive performance is still a poorly explored field of research in the context of peripheral signal molecules. We focused on whether exercise training might be an effective approach in regulating peripheral CTSB and whether there is a relationship between shifts in exercise-induced CTSB levels and cognitive functions. Although half of the studies included in this review noted that exercise improved cognitive functions and enhanced peripheral CTSB levels, this does not imply that increased peripheral CTSB levels is the exact mechanism by which exercise triggers cognitive benefits. Since this literature is still sparse, further experimental research is needed to better comprehend the effects of exercise on CTSB and cognitive functions.

Supplemental Material

Supplemental Material - The Relationship Between Exercise, Cathepsin B, and Cognitive Functions: Systematic Review

Supplemental Material for The Relationship Between Exercise, Cathepsin B, and Cognitive Functions: Systematic Review by Evrim Gökçe, and Neslişah Gün

Footnotes

Acknowledgments

We sincerely thank the authors of the included studies in this review due to contributing this research field.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Evrim Gökçe

Data Availability Statement

Data in this study are available on request from the authors.

Supplemental Material

Supplemental material for this article is available online.

Author Biographies

Evrim Gökçe is a researcher at Ankara City Hospital, Sports Rehabilitation Laboratory. She has a PhD in physiology. She is working on the relationship between exercise and the brain.

Neslişah Gün is an assistant professor at Kırklareli University, Faculty of Health Sciences. She has PhD degree in Physical Therapy and Rehabilitation.

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