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Review
. 2024 Jul;31(3):204-224.
doi: 10.1177/09727531231192759. Epub 2024 Jan 10.

The Effects of Physical Activity on Experimental Models of Vascular Dementia: A Systematic Review and Meta-Analysis

Ifechukwude J Biose  1 , Wesley H Chastain  2 , Rebecca J Solch-Ottaiano  3 , Viktoriya S Grayson  2 , Hanyun Wang  1 , Somdeb Banerjee  2 , Gregory J Bix  3   4   5   6   7
Affiliations
Review

The Effects of Physical Activity on Experimental Models of Vascular Dementia: A Systematic Review and Meta-Analysis

Ifechukwude J Biose et al. Ann Neurosci. 2024 Jul.

Abstract

Background: Physical activity is associated with improved brain health and cognition in humans. However, the validity, range, and quality of evidence for the beneficial outcomes linked to exercise in experimental models of vascular dementia (VaD) have not been evaluated. We performed a systematic review and meta-analysis of studies that assessed the effect of exercise intervention on models of VaD to provide an unbiased and comprehensive determination of the cognitive function and brain morphology benefits of exercise.

Summary: A systematic search in three databases as well as study design characteristics and experimental data extraction were completed in December 2021. We investigated the effects of exercise on cognitive function and brain-morphology outcomes in VaD models. Twenty-five studies were included for systematic review, while 21 studies were included in the meta-analysis. These studies included seven models of VaD in rats (60%, 15 studies), mice (36%, 9 studies), and pigs (4%, 1 study). None of the included studies used aged animals, and the majority of studies (80%) used only male animals.

Key message exercise improves cognition but increased neuro-inflammation in vad models: Exercise improved cognitive function as well as some markers of brain morphology in models of VaD. However, exercise increased anxiety and neuro-inflammatory signals in VaD models. Further, we observed increased reporting anomalies such as a lack of blinding to group treatment or data analysis and randomization of animals to groups. Our report could help in the appropriate design of experimental studies seeking to investigate the effects of exercise as a non-pharmacological intervention on VaD models with a high translational impact.

Keywords: Physical activity; cognitive function; meta-analysis; preclinical; systematic review; vascular dementia.

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Conflict of interest statement

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

Figures

Figure 1.
Figure 1.. PRISMA Flow diagram for Study Selection, Showing the Number of Studies Identified, Screened, and Included for Descriptive Assessment, Meta-Analysis, and Study Quality Evaluation.
Figure 2.
Figure 2.. (A) Meta-Analysis of Novel Object Location and Recognition Test. Dong a, Involuntary Exercise Group; Dong b, Forced Exercise Group; Dong c, Voluntary Exercise Group; Lin d, Involuntary Exercise Group; Lin e, Forced Exercise Group; Lin f, Voluntary Exercise Group; Moreira a, Running Wheel; Moreira b, Female Enriched Environment; Moreira c, Male Enriched Environment. Trigiani a, Cohort 1; Trigiani b, Cohort 2. (B) Meta-Analysis of Morris Water Maze Probe. Cechetti b, Post-Surgery Exercise; Cechetti, c Pre- and Post-Surgery Exercise; Trigiani a, Cohort 1; Trigiani b, Cohort 2. (C) Meta-analysis of Morris Water Maze latency (seconds). Cechetti a, Pre-Surgery Exercise; Cechetti b, Post-Surgery Exercise; Cechetti, c Pre- and Post-Surgery Exercise; Trigiani a, Cohort 1; Trigiani b, Cohort 2. (D) Meta-Analysis of Passive avoidance. (E) Meta-Analysis of Y-maze (percent spontaneous alterations). Graham a, Chow; Graham b, Western Diet. (F) Meta-Analysis of Open Field.
Figure 2.
Figure 2.. (A) Meta-Analysis of Novel Object Location and Recognition Test. Dong a, Involuntary Exercise Group; Dong b, Forced Exercise Group; Dong c, Voluntary Exercise Group; Lin d, Involuntary Exercise Group; Lin e, Forced Exercise Group; Lin f, Voluntary Exercise Group; Moreira a, Running Wheel; Moreira b, Female Enriched Environment; Moreira c, Male Enriched Environment. Trigiani a, Cohort 1; Trigiani b, Cohort 2. (B) Meta-Analysis of Morris Water Maze Probe. Cechetti b, Post-Surgery Exercise; Cechetti, c Pre- and Post-Surgery Exercise; Trigiani a, Cohort 1; Trigiani b, Cohort 2. (C) Meta-analysis of Morris Water Maze latency (seconds). Cechetti a, Pre-Surgery Exercise; Cechetti b, Post-Surgery Exercise; Cechetti, c Pre- and Post-Surgery Exercise; Trigiani a, Cohort 1; Trigiani b, Cohort 2. (D) Meta-Analysis of Passive avoidance. (E) Meta-Analysis of Y-maze (percent spontaneous alterations). Graham a, Chow; Graham b, Western Diet. (F) Meta-Analysis of Open Field.
Figure 2.
Figure 2.. (A) Meta-Analysis of Novel Object Location and Recognition Test. Dong a, Involuntary Exercise Group; Dong b, Forced Exercise Group; Dong c, Voluntary Exercise Group; Lin d, Involuntary Exercise Group; Lin e, Forced Exercise Group; Lin f, Voluntary Exercise Group; Moreira a, Running Wheel; Moreira b, Female Enriched Environment; Moreira c, Male Enriched Environment. Trigiani a, Cohort 1; Trigiani b, Cohort 2. (B) Meta-Analysis of Morris Water Maze Probe. Cechetti b, Post-Surgery Exercise; Cechetti, c Pre- and Post-Surgery Exercise; Trigiani a, Cohort 1; Trigiani b, Cohort 2. (C) Meta-analysis of Morris Water Maze latency (seconds). Cechetti a, Pre-Surgery Exercise; Cechetti b, Post-Surgery Exercise; Cechetti, c Pre- and Post-Surgery Exercise; Trigiani a, Cohort 1; Trigiani b, Cohort 2. (D) Meta-Analysis of Passive avoidance. (E) Meta-Analysis of Y-maze (percent spontaneous alterations). Graham a, Chow; Graham b, Western Diet. (F) Meta-Analysis of Open Field.
Figure 3.
Figure 3.. (A) Meta-Analysis of Neuroinflammation Markers. Graham a, Chow; Graham b, Western Diet; Trigiani a, Cohort 1; Trigiani b, Cohort 2. (B) Meta-Analysis of Markers of White Matter Integrity. Hase a, 3 h Environmental Enrichment; Hase b, Full-Time Environmental Enrichment. Data Used in the Analysis Were Total Number of Oligodendrocytes in the Corpus Callosum and Western Blot of Myelin Basic Protein. (C) Meta-Analysis of Markers of Neuronal Synaptic Transmission. Dong a, Involuntary Exercise Group; Dong b, Forced Exercise Group; Dong c, Voluntary Exercise Group; Lin d, Involuntary Exercise Group; Lin e, Forced Exercise Group; Lin f, Voluntary Exercise Group. (D) Meta-Analysis of Markers of Cellular Integrity. Dong a, Involuntary Exercise Group; Dong b, Forced Exercise Group; Dong c, Voluntary Exercise Group; Lin d, Involuntary Exercise Group; Lin e, Forced Exercise Group; Lin f, Voluntary Exercise Group. (E) Meta-analysis of Western Blots of Brain-Derived Neurotrophic Factor. Lin a, Involuntary Exercise Group; Lin b, Forced Exercise Group; Lin c, Voluntary Exercise Group. (F) Meta-Analysis of Cell Proliferation. Trigiani a, Cohort 1; Trigiani b, Cohort 2. brdU.
Figure 3.
Figure 3.. (A) Meta-Analysis of Neuroinflammation Markers. Graham a, Chow; Graham b, Western Diet; Trigiani a, Cohort 1; Trigiani b, Cohort 2. (B) Meta-Analysis of Markers of White Matter Integrity. Hase a, 3 h Environmental Enrichment; Hase b, Full-Time Environmental Enrichment. Data Used in the Analysis Were Total Number of Oligodendrocytes in the Corpus Callosum and Western Blot of Myelin Basic Protein. (C) Meta-Analysis of Markers of Neuronal Synaptic Transmission. Dong a, Involuntary Exercise Group; Dong b, Forced Exercise Group; Dong c, Voluntary Exercise Group; Lin d, Involuntary Exercise Group; Lin e, Forced Exercise Group; Lin f, Voluntary Exercise Group. (D) Meta-Analysis of Markers of Cellular Integrity. Dong a, Involuntary Exercise Group; Dong b, Forced Exercise Group; Dong c, Voluntary Exercise Group; Lin d, Involuntary Exercise Group; Lin e, Forced Exercise Group; Lin f, Voluntary Exercise Group. (E) Meta-analysis of Western Blots of Brain-Derived Neurotrophic Factor. Lin a, Involuntary Exercise Group; Lin b, Forced Exercise Group; Lin c, Voluntary Exercise Group. (F) Meta-Analysis of Cell Proliferation. Trigiani a, Cohort 1; Trigiani b, Cohort 2. brdU.
Figure 4.
Figure 4.. Forest Plots of Exercise Type Effects on Cognitive Function (A) and Brain Morphology (B) Following Vascular Dementia Modeling in Animals. The Size of the Square Represents the Weight.
Figure 5.
Figure 5.. Study Quality. Summary of the Quality of the 25 Included Studies Based on (A) Reporting Quality Criteria and (B) the Risk of Bias Assessment Specified Reporting and/ or Methodological Quality Criteria. The Number of Studies Assessed for Quality are Indicated Within Colored Zone of the Bars, With the Exception of the “Unclear” Category in Panel (B) for Clarity.
Figure 6.
Figure 6.. Publication Bias. Evaluation of Publication Bias in Outcome Effects of Exercise Intervention Following the Induction of Vascular Dementia Models. (A) The Funnel Plot for Cognitive Function Data Suggests Plot Symmetry Indicating the Absence of Publication Bias. (B) The Funnel Plot of Effect of Exercise on Brain Morphology Shows Asymmetrical Plots Which Suggests the Presence of Publication Bias. (C) The Funnel Plot of Combined Data for Cognitive Function and Brain Morphology Effects Suggests Symmetrical Plots and, Hence Absence of the Publication Bias. The Vertical Red Line Represents the Overall Effect Size. The Gray Lines Indicate the Statistical Significance of Effect Sizes of Cohort Comparisons. Reporting of a Statement Regarding Potential Conflict of Interests and Compliance With Animal Welfare Regulations Were Extracted, But They Were Not Part of the Overall Risk of Bias.
Figure 6.
Figure 6.. Publication Bias. Evaluation of Publication Bias in Outcome Effects of Exercise Intervention Following the Induction of Vascular Dementia Models. (A) The Funnel Plot for Cognitive Function Data Suggests Plot Symmetry Indicating the Absence of Publication Bias. (B) The Funnel Plot of Effect of Exercise on Brain Morphology Shows Asymmetrical Plots Which Suggests the Presence of Publication Bias. (C) The Funnel Plot of Combined Data for Cognitive Function and Brain Morphology Effects Suggests Symmetrical Plots and, Hence Absence of the Publication Bias. The Vertical Red Line Represents the Overall Effect Size. The Gray Lines Indicate the Statistical Significance of Effect Sizes of Cohort Comparisons. Reporting of a Statement Regarding Potential Conflict of Interests and Compliance With Animal Welfare Regulations Were Extracted, But They Were Not Part of the Overall Risk of Bias.
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