CoChat
Sign Up
Cited by 160Dementia and Cognitive Impairment ResearchPhysical Activity and HealthAlzheimer's disease research and treatments

The DOI matches its Crossref record; 136 of the 136 references it cites were found in a registry or an index.

Effects of Aerobic Exercise Training on Systemic Biomarkers and Cognition in Late Middle-Aged Adults at Risk for Alzheimer’s Disease

Open access
Gaitán, Julian M., Moon, Hyo Youl, Stremlau, Matthew, Dubal, Dena B., Cook, Dane B., Okonkwo, Ozioma C., van Praag, Henriette·2021·Frontiers in Endocrinology
DOI 10.3389/fendo.2021.660181PMC PMC8173166
Open this paper in CoChat — free accountOpen PDF

Abstract

Increasing evidence indicates that physical activity and exercise training may delay or prevent the onset of Alzheimer’s disease (AD). However, systemic biomarkers that can measure exercise effects on brain function and that link to relevant metabolic responses are lacking. To begin to address this issue, we utilized blood samples of 23 asymptomatic late middle-aged adults, with familial and genetic risk for AD (mean age 65 years old, 50% female) who underwent 26 weeks of supervised treadmill training. Systemic biomarkers implicated in learning and memory, including the myokine Cathepsin B (CTSB), brain-derived neurotrophic factor (BDNF), and klotho, as well as metabolomics were evaluated. Here we show that aerobic exercise training increases plasma CTSB and that changes in CTSB, but not BDNF or klotho, correlate with cognitive performance. BDNF levels decreased with exercise training. Klotho levels were unchanged by training, but closely associated with change in VO 2 peak. Metabolomic analysis revealed increased levels of polyunsaturated free fatty acids (PUFAs), reductions in ceramides, sphingo- and phospholipids, as well as changes in gut microbiome metabolites and redox homeostasis, with exercise. Multiple metabolites (~30%) correlated with changes in BDNF, but not CSTB or klotho. The positive association between CTSB and cognition, and the modulation of lipid metabolites implicated in dementia, support the beneficial effects of exercise training on brain function. Overall, our analyses indicate metabolic regulation of exercise-induced plasma BDNF changes and provide evidence that CTSB is a marker of cognitive changes in late middle-aged adults at risk for dementia.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.3389/fendo.2021.660181

Cites

136 of 136 references verified0 citation errors · 0 not checkable

Statistics

Figures

Figure 1 Study design and effects of exercise on circulating biomarkers. (A) Overview of study design, exercise training intervention [Usual Physical activity (UPA) or Enhanced Physical Activity (EPA)], and blood sample analyses. The list of outcomes is specific to the present report; other outcomes were measured as part of the trial and are described elsewhere (35). (B–D) Effects of the 26-week aerobic exercise intervention on systemic biomarkers. (B) Plasma CTSB increased in the EPA group post-intervention as compared to baseline. (C) Plasma BNDF decreased in the EPA group. (D) Serum klotho levels did not change with exercise. (E) Plasma-derived metabolites by super pathway. ** p < 0.01 Cathepsin B (CTSB); brain-derived neurotrophic factor (BDNF); Usual Physical Activity (UPA); Enhanced Physical Activity (EPA).
Figure 1 Study design and effects of exercise on circulating biomarkers. (A) Overview of study design, exercise training intervention [Usual Physical activity (UPA) or Enhanced Physical Activity (EPA)], and blood sample analyses. The list of outcomes is specific to the present report; other outcomes were measured as part of the trial and are described elsewhere (35). (B–D) Effects of the 26-week aerobic exercise intervention on systemic biomarkers. (B) Plasma CTSB increased in the EPA group post-intervention as compared to baseline. (C) Plasma BNDF decreased in the EPA group. (D) Serum klotho levels did not change with exercise. (E) Plasma-derived metabolites by super pathway. ** p < 0.01 Cathepsin B (CTSB); brain-derived neurotrophic factor (BDNF); Usual Physical Activity (UPA); Enhanced Physical Activity (EPA).CC BY · PubMed Central
Figure 2 Correlations between changes in systemic biomarkers with cognitive and cardiorespiratory fitness measures. (A) Change in CTSB was significantly correlated with verbal learning and memory assessed by the CVLT Total recall score. (B) Change in CTSB was correlated, albeit not significantly, with executive function on the D-KEFS CWI. (C) There was no correlation between CTSB change and cardiorespiratory fitness. (D–F) Change in BDNF was not significantly correlated with cognitive performance or cardiorespiratory fitness. (G, H) Change in klotho was not significantly correlated with cognitive performance. (I) Change in klotho was significantly correlated with cardiorespiratory fitness. A decrease in the raw D-KEFS CWI scores indicates improvement on this outcome, so D-KEFS CWI scores were inverted such that a positive change indicates improvement in this figure. * p <.05. Usual Physical Activity (UPA); Enhanced Physical Activity (EPA); cathepsin B (CTSB); brain-derived neurotrophic factor (BDNF); cardiorespiratory fitness (VO2peak); California Verbal Learning Test (CVLT); Delis-Kaplan Executive Function System Color-Word Interference (D-KEFS CWI).
Figure 2 Correlations between changes in systemic biomarkers with cognitive and cardiorespiratory fitness measures. (A) Change in CTSB was significantly correlated with verbal learning and memory assessed by the CVLT Total recall score. (B) Change in CTSB was correlated, albeit not significantly, with executive function on the D-KEFS CWI. (C) There was no correlation between CTSB change and cardiorespiratory fitness. (D–F) Change in BDNF was not significantly correlated with cognitive performance or cardiorespiratory fitness. (G, H) Change in klotho was not significantly correlated with cognitive performance. (I) Change in klotho was significantly correlated with cardiorespiratory fitness. A decrease in the raw D-KEFS CWI scores indicates improvement on this outcome, so D-KEFS CWI scores were inverted such that a positive change indicates improvement in this figure. * p <.05. Usual Physical Activity (UPA); Enhanced Physical Activity (EPA); cathepsin B (CTSB); brain-derived neurotrophic factor (BDNF); cardiorespiratory fitness (VO2peak); California Verbal Learning Test (CVLT); Delis-Kaplan Executive Function System Color-Word Interference (D-KEFS CWI).CC BY · PubMed Central
Figure 3 Changes in sphingolipid metabolism and BDNF. (A, C, E) Changes in (A) sphingosine (C) spinganine and (E) sphinganine-1-phosphate correlated closely with change in BDNF. (B, D, F) Box plots showing levels of these three metabolites were reduced post-intervention in the EPA group. (G) Schematic pathway of sphingolipid metabolism. Raw metabolite values were normalized in terms of raw area counts by log transformation and rescaled to set the median equal to 1. *p < .05. brain-derived neurotrophic factor (BDNF); Usual Physical Activity (UPA); Enhanced Physical Activity (EPA).
Figure 3 Changes in sphingolipid metabolism and BDNF. (A, C, E) Changes in (A) sphingosine (C) spinganine and (E) sphinganine-1-phosphate correlated closely with change in BDNF. (B, D, F) Box plots showing levels of these three metabolites were reduced post-intervention in the EPA group. (G) Schematic pathway of sphingolipid metabolism. Raw metabolite values were normalized in terms of raw area counts by log transformation and rescaled to set the median equal to 1. *p < .05. brain-derived neurotrophic factor (BDNF); Usual Physical Activity (UPA); Enhanced Physical Activity (EPA).CC BY · PubMed Central
Figure 4 Alterations in phospholipid metabolism and BDNF. (A, C, E) Changes in (A) glycero-phosphoethanolamine (C) phosphoethanolamine and (E) choline phosphate correlated closely with change in BDNF. (B, D, F) Box plots showing levels of these three metabolites were reduced post-intervention in the EPA group. (G) Schematic of the phospholipid metabolic pathway. Raw metabolite values were normalized in terms of raw area counts by log transformation and rescaled to set the median equal to 1. *p < .05. brain-derived neurotrophic factor (BDNF); Usual Physical Activity (UPA); Enhanced Physical Activity (EPA).
Figure 4 Alterations in phospholipid metabolism and BDNF. (A, C, E) Changes in (A) glycero-phosphoethanolamine (C) phosphoethanolamine and (E) choline phosphate correlated closely with change in BDNF. (B, D, F) Box plots showing levels of these three metabolites were reduced post-intervention in the EPA group. (G) Schematic of the phospholipid metabolic pathway. Raw metabolite values were normalized in terms of raw area counts by log transformation and rescaled to set the median equal to 1. *p < .05. brain-derived neurotrophic factor (BDNF); Usual Physical Activity (UPA); Enhanced Physical Activity (EPA).CC BY · PubMed Central
Figure 5 Changes in markers of oxidative stress and BDNF. (A) Schematic of the redox pathway. (B–D) Exercise training resulted in changes in redox homeostasis with an increase in (B) methionine sulfoxide, and decreases in (C) taurine and (D) hypotaurine. Changes in (E) taurine and (F) hypotaurine were closely associated with changes in BDNF. Raw metabolite values were normalized in terms of raw area counts by log transformation and rescaled to set the median equal to 1. *p < .05. brain-derived neurotrophic factor (BDNF); Usual Physical Activity (UPA); Enhanced Physical Activity (EPA).
Figure 5 Changes in markers of oxidative stress and BDNF. (A) Schematic of the redox pathway. (B–D) Exercise training resulted in changes in redox homeostasis with an increase in (B) methionine sulfoxide, and decreases in (C) taurine and (D) hypotaurine. Changes in (E) taurine and (F) hypotaurine were closely associated with changes in BDNF. Raw metabolite values were normalized in terms of raw area counts by log transformation and rescaled to set the median equal to 1. *p < .05. brain-derived neurotrophic factor (BDNF); Usual Physical Activity (UPA); Enhanced Physical Activity (EPA).CC BY · PubMed Central
Figure 6 Differences in molecules originating from the gut microbiome, and BDNF and CTSB (A) Change in CTSB was significantly associated with a change indoleproprionate (IPA), but not with (B) serotonin. (C) Change in BDNF showed a weak but non-significant correlation with IPA and (D) a significant correlation with serotonin. (E) IPA and (F) serotonin levels were lower post-intervention in the EPA group. Raw metabolite values were normalized in terms of raw area counts by log transformation and rescaled to set the median equal to 1. † .05 < p < .10. cathepsin B (CTSB); brain-derived neurotrophic factor (BDNF); Usual Physical Activity (UPA); Enhanced Physical Activity (EPA).
Figure 6 Differences in molecules originating from the gut microbiome, and BDNF and CTSB (A) Change in CTSB was significantly associated with a change indoleproprionate (IPA), but not with (B) serotonin. (C) Change in BDNF showed a weak but non-significant correlation with IPA and (D) a significant correlation with serotonin. (E) IPA and (F) serotonin levels were lower post-intervention in the EPA group. Raw metabolite values were normalized in terms of raw area counts by log transformation and rescaled to set the median equal to 1. † .05 < p < .10. cathepsin B (CTSB); brain-derived neurotrophic factor (BDNF); Usual Physical Activity (UPA); Enhanced Physical Activity (EPA).CC BY · PubMed Central

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Research works printed but not linked: 1

  1. 2018, Acsm’s Guidelines for Exercise Testing and Prescription

Cited by

Sorted by citations

See all 160

Related

See all

Metadata

Authors
Gaitán, J. M., Moon, H. Y., Stremlau, M., Dubal, D. B., Cook, D. B., Okonkwo, O. C., & van Praag, H.
Affiliations
  • University of Wisconsin–Madison (US)
  • Seoul National University (KR)
  • National Institute on Aging (US)
  • University of California, San Francisco (US)
Corresponding author
Okonkwo, Ozioma C.
ORCID
Venue
Frontiers in Endocrinology
Publisher
Frontiers Media SA
Published
2021-05-20
Volume
12
Pages
660181-660181
ISSN
1664-2392 (ISSN-L)
DOI
10.3389/fendo.2021.660181
PMC
PMC8173166
OpenAlex
W3161410779
Cited by
160
References
136
Citations by year
2026: 39 · 2025: 33 · 2024: 32 · 2023: 34 · 2022: 20 · 2021: 2
FWCI
15.77
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Endocrinology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Seoul National University Open Repository (Seoul National University) (submittedVersion)
Funders
  • Alzheimer's Association
  • Extendicare Foundation
  • National Institutes of Health
  • Florida Department of Health
  • National Institute on Aging
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Physical Activity and Health
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
Keywords
aerobic exercise training, Alzheimer's disease risk, systemic biomarkers, cathepsin B, brain-derived neurotrophic factor, Klotho, cognitive performance, metabolomics, lipid metabolism, polyunsaturated fatty acids, ceramide, gut microbiota metabolites, redox homeostasis, peak oxygen uptake, treadmill training, middle-aged adults, dementia prevention
MeSH terms
Gastrointestinal Microbiome, Klotho Proteins, Aged, Aged, 80 and over, Alzheimer Disease, Cathepsin B, Cognition, Female, Humans, Hydroxyproline, Male, Middle Aged, Proline, Risk Factors, Biomarkers, Exercise, Fatty Acids, Omega-3, Brain-Derived Neurotrophic Factor, Lipid Metabolism, Metabolomics

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review