Subcortical Ischemic Vascular Cognitive Impairment Research Articles

Can exercise benefit cerebral white matter myelin? Findings from a 12‐month randomized controlled trial in older adults with vascular cognitive impairment

AbstractBackgroundCerebral small vessel disease is a major underlying cause of subcortical ischemic vascular cognitive impairment (SIVCI). Myelin loss is a feature of cerebral small vessel disease, which may underly cognitive and functional decline in older adults living with SIVCI. Resistance training (RT) is a form of exercise associated with slower progression of white matter lesions, a cerebral small vessel disease marker. However, it remains to be determined whether RT can counteract myelin loss in individuals living with SIVCI. Thus, we examined the impact of a 12‐month, twice‐weekly progressive RT program on myelin content in those with SIVCI.MethodThis was a sub‐study of a 12‐month single‐blinded, randomized controlled trial. Participants (n = 91) were randomized to RT or an active control group (balance and tone exercises [BAT]). Study eligibility included: 1) age 55 years and older; 2) magnetic resonance imaging (MRI) evidence of cerebral small vessel disease; 3) mild cognitive impairment; and 4) the absence of dementia. Myelin was measured using a multi‐echo gradient and spin echo T2 relaxation MRI sequence, indexed as myelin water fraction (MWF). Differences between groups at 12 months were assessed via analysis of covariance adjusting for baseline MWF and estimated intracranial volume. MWF data from fifteen white matter tracts were analyzed. Post‐hoc regressions were conducted to determine if changes in MWF were associated with changes in mobility measured with the Short Physical Performance Battery (SPPB).ResultSeventy‐three participants (RT = 36) aged 74.1 (SD = 5.7), 64% females with high‐quality MRI data were included in the analyses. At 12 months, RT showed lower MWF levels compared with BAT in the genu of the corpus callosum (estimated mean difference [RT – BAT]: ‐0.610, 95% CI: ‐1.041 to ‐0.178, p = 0.006), fornix (‐0.883, 95% CI: ‐1.570 to ‐0.197, p = 0.012), and combined white matter tracts (‐0.326, 95% CI: ‐0.643 to ‐0.009, p = 0.044). Changes in MWF in the combined white matter tracs were positively associated with changes in SPPB (Unstandardized B = 0.124, SE = 0.061, p = 0.047).ConclusionContrary to our expectations, 12 months of balance and tone exercises, but not RT, showed positive changes in myelin. These improvements may result in better mobility in older adults with SIVCI.

Aerobic exercise improves executive functions in females, but not males, without the BDNF Val66Met polymorphism

BackgroundAerobic exercise promotes cognitive function in older adults; however, variability exists in the degree of benefit. The brain-derived neurotropic factor (BDNF) Val66Met polymorphism and biological sex are biological factors that have been proposed as important modifiers of exercise efficacy. Therefore, we assessed whether the effect of aerobic exercise on executive functions was dependent on the BDNFval66met genotype and biological sex.MethodsWe used data from a single-blind randomized controlled trial in older adults with subcortical ischemic vascular cognitive impairment (NCT01027858). Fifty-eight older adults were randomly assigned to either the 6 months, three times per week progressive aerobic training (AT) group or the usual care plus education control (CON) group. The secondary aim of the parent study included executive functions which were assessed with the Trail Making Test (B–A) and the Digit Symbol Substitution Test at baseline and trial completion at 6 months.ResultsAnalysis of covariance, controlling for baseline global cognition and baseline executive functions performance (Trail Making Test or Digit Symbol Substitution Test), tested the three-way interaction between experimental group (AT, CON), BDNFval66met genotype (Val/Val carrier, Met carrier), and biological sex (female, male). Significant three-way interactions were found for the Trail Making Test (F(1,48) = 4.412, p < 0.04) and Digit Symbol Substitution Test (F(1,47) = 10.833, p < 0.002). Posthoc analyses showed female Val/Val carriers benefited the most from 6 months of AT compared with CON for Trail Making Test and Digit Symbol Substitution Test performance. Compared with CON, AT did not improve Trail Making Test performance in male Val/Val carriers or Digit Symbol Substitution Test performance in female Met carriers.ConclusionsThese results suggest that future randomized controlled trials should take into consideration BDNF genotype and biological sex to better understand the beneficial effects of AT on cognitive function in vascular cognitive impairment to maximize the beneficial effects of exercise and help establish exercise as medicine for cognitive health.

Study of gray matter atrophy pattern with subcortical ischemic vascular disease-vascular cognitive impairment no dementia based on structural magnetic resonance imaging.

This study explored the structural imaging changes in patients with subcortical ischemic vascular disease (SIVD)-vascular cognitive impairment no dementia (VCIND) and the correlation between the changes in gray matter volume and the field of cognitive impairment to provide new targets for early diagnosis and treatment. Our study included 15 patients with SIVD-normal cognitive impairment (SIVD-NCI), 63 with SIVD-VCIND, 26 with SIVD-vascular dementia (SIVD-VD), and 14 normal controls (NC). T1-weighted images of all participants were collected, and DPABI and SPM12 software were used to process the gray matter of the four groups based on voxels. Fisher's exact test, one-way ANOVA and Kruskal-Wallis H test were used to evaluate all clinical and demographic data and compare the characteristics of diencephalic gray matter atrophy in each group. Finally, the region of interest (ROI) of the SIVD-VCIND was extracted, and Pearson correlation analysis was performed between the ROI and the results of the neuropsychological scale. Compared to the NC, changes in gray matter atrophy were observed in the bilateral orbitofrontal gyrus, right middle temporal gyrus, superior temporal gyrus, and precuneus in the SIVD-VCIND. Gray matter atrophy was observed in the left cerebellar region 6, cerebellar crural region 1, bilateral thalamus, right precuneus, and calcarine in the SIVD-VD. Compared with the SIVD-VCIND, gray matter atrophy changes were observed in the bilateral thalamus in the SIVD-VD (p < 0.05, family-wise error corrected). In the SIVD-VCIND, the total gray matter volume, bilateral medial orbital superior frontal gyrus, right superior temporal gyrus, middle temporal gyrus, and precuneus were positively correlated with Boston Naming Test score, whereas the total gray matter volume, right superior temporal gyrus, and middle temporal gyrus were positively correlated with overall cognition. Structural magnetic resonance imaging can detect extensive and subtle structural changes in the gray matter of patients with SIVD-VCIND and SIVD-VD, providing valuable evidences to explain the pathogenesis of subcortical vascular cognitive impairment and contributing to the early diagnosis of SIVD-VCIND and early warning of SIVD-VD.

Progressive alteration of dynamic functional connectivity patterns in subcortical ischemic vascular cognitive impairment patients

Alterations in the temporal evolution of brain states in the process of cognitive impairment aggravation due to subcortical ischemic vascular disease (SIVD) is not understood. The dynamic functional connectivity was investigated to identify the abnormal temporal properties of brain states associated with cognitive impairment caused by SIVD. Eighteen patients with subcortical ischemic vascular cognitive impairment with no dementia (SIVCIND), 19 dementia patients (SIVaD) and 26 normal controls were enrolled. We found that the occupancy rate and mean lifetime of brain states were associated with cognitive performance. SIVCIND had a higher occupancy rate and longer mean lifetime in weakly connected states than normal controls. SIVaD had similar but more extensive changes in the temporal properties of brain states. In addition, switching from weakly connected states to more strongly connected states was more difficult in SIVCIND and SIVaD patients than in normal controls, especially in SIVaD patients. The results revealed that not only the transition to but also maintenance in strongly connected states became increasingly difficult when SIVD-related cognitive impairment progressed into a more severe stage.

Diagnosis of Subcortical Ischemic Vascular Cognitive Impairment With No Dementia Using Radiomics of Cerebral Cortex and Subcortical Nuclei in High-Resolution T1-Weighted MR Imaging.

PurposeTo investigate whether the combination of radiomics derived from brain high-resolution T1-weighted imaging and automatic machine learning could diagnose subcortical ischemic vascular cognitive impairment with no dementia (SIVCIND) accurately.MethodsA total of 116 right-handed participants involving 40 SIVCIND patients and 76 gender-, age-, and educational experience-matched normal controls (NM) were recruited. A total of 7,106 quantitative features from the bilateral thalamus, hippocampus, globus pallidus, amygdala, nucleus accumbens, putamen, caudate nucleus, and 148 areas of the cerebral cortex were automatically calculated from each subject. Six methods including least absolute shrinkage and selection operator (LASSO) were utilized to lessen the redundancy of features. Three supervised machine learning approaches of logistic regression (LR), random forest (RF), and support vector machine (SVM) employing 5-fold cross-validation were used to train and establish diagnosis models, and 10 times 10-fold cross-validation was used to evaluate the generalization performance of each model. Correlation analysis was performed between the optimal features and the neuropsychological scores of the SIVCIND patients.ResultsThirteen features from the right amygdala, right hippocampus, left caudate nucleus, left putamen, left thalamus, and bilateral nucleus accumbens were included in the optimal subset. Among all the three models, the RF produced the highest diagnostic performance with an area under the receiver operator characteristic curve (AUC) of 0.990 and an accuracy of 0.948. According to the correlation analysis, the radiomics features of the right amygdala, left caudate nucleus, left putamen, and left thalamus were found to be significantly correlated with the neuropsychological scores of the SIVCIND patients.ConclusionsThe combination of radiomics derived from brain high-resolution T1-weighted imaging and machine learning could diagnose SIVCIND accurately and automatically. The optimal radiomics features are mostly located in the right amygdala, left caudate nucleus, left putamen, and left thalamus, which might be new biomarkers of SIVCIND.

Cardiovascular risk moderates aerobic exercise efficacy on executive function in subcortical ischemic vascular cognitive impairment

AbstractBackgroundAerobic exercise can promote cognitive function in adults with Subcortical Ischemic Vascular Cognitive Impairment (SIVCI) by modifying cardiovascular risk factors. However, one’s cardiovascular health may attenuate the benefits of aerobic exercise on cognitive outcomes in SIVCI. We examined whether baseline Framingham Cardiovascular Risk Profile Score (FCRP) moderates the effect of a 6‐month progressive aerobic exercise program on executive function in adults with SIVCI.MethodA secondary analysis of a proof‐of‐concept randomized controlled trial in 71 adults, who were randomized to either: 1) 3x/week progressive aerobic exercise program (AT); or 2) education program (CON). Three executive processes were measured: 1) response inhibition by Stroop Colour Word Test; 2) working memory by digits backward test, and 3) set shifting by the Trail Making Test (B‐A). Baseline cardiovascular risk was calculated using the FCRP, and participants were classified as either low risk (&lt;20% FCRP score; LCVR) or high risk (&gt;20% FCRP score; HCVR). A complete case analysis (n=57) was conducted using an analysis of covariance (ANCOVA) to evaluate between‐group differences in the three executive processes. Age, baseline Montreal Cognitive Assessment score, education, and baseline score for the outcome variable were entered as covariates in all models.ResultA significant interaction was found between FCRP and group (AT or CON) for the digit span backward (F(1,49)=4.67, p=0.03) and the Trail Making Test (F(1,50)=4.09, p=0.04). On the digit span backward test, AT improved performance compared to CON (3.74±.33 vs. 2.75±.46) in those with LCVR, while in those with HCVR, AT did not improve performance compared to CON (2.97±.45 vs. 3.76±.41). Similarly, for the Trail Making Test (B‐A), AT improved performance compared to CON (52.66±13.27 vs. 80.12±17.82) in those with LCVR, while AT was not beneficial compared to CON in those with HCVR (98.80±18.06 vs. 59.92±17.09).ConclusionBaseline cardiovascular risk significantly moderates the efficacy of aerobic exercise on working memory and set shifting in adults with SIVCI. Our findings highlight the importance of intervening early in the disease course of SIVCI, when cardiovascular risk may be lower, to reap maximum benefits of aerobic exercise.

Cardiovascular risk moderates the effect of aerobic exercise on executive functions in older adults with subcortical ischemic vascular cognitive impairment

Aerobic training (AT) can promote cognitive function in adults with Subcortical Ischemic Vascular Cognitive Impairment (SIVCI) by modifying cardiovascular risk factors. However, pre-existing cardiovascular health may attenuate the benefits of AT on cognitive outcomes in SIVCI. We examined whether baseline cardiovascular risk moderates the effect of a 6-month progressive AT program on executive functions with a secondary analysis of a randomized controlled trial in 71 adults, who were randomized to either: (1) 3×/week progressive AT; or (2) education program (CON). Three executive processes were measured: (1) response inhibition by Stroop Test; (2) working memory by digits backward test; and (3) set shifting by the Trail Making Test. Baseline cardiovascular risk was calculated using the Framingham cardiovascular disease (CVD) Risk Score (FCRS), and participants were classified as either low risk (< 20% FCRS score; LCVR) or high risk (≥ 20% FCRS score; HCVR). A complete case analysis (n = 58) was conducted using an analysis of covariance (ANCOVA) to evaluate between-group differences in the three executive processes. A significant interaction was found between cardiovascular risk group and intervention group (AT or CON) for the digit span backward and the Trail Making Test. AT improved performance compared with CON in those with LCVR, while in those with HCVR, AT did not improve performance compared with CON. Baseline cardiovascular risk significantly moderates the efficacy of AT on cognition. Our findings highlight the importance of intervening early in the disease course of SIVCI, when cardiovascular risk may be lower, to reap maximum benefits of aerobic exercise.

Reaction Time Decomposition as a Tool to Study Subcortical Ischemic Vascular Cognitive Impairment.

Background:The study of reaction time (RT) and its intraindividual variability (IIV) in aging, cognitive impairment, and dementia typically fails to investigate the processing stages that contribute to an overall response. Applying “mental chronometry” techniques makes it possible to separately assess the role of processing components during environmental interaction.Objective:To determine whether RT and IIV-decomposition techniques can shed light on the nature of underlying deficits in subcortical ischemic vascular cognitive impairment (VCI). Using a novel iPad task, we examined whether VCI deficits occur during both initiation and movement phases of a response, and whether they are equally reflected in both RT and IIV.Methods:Touch cancellation RT and its IIV were measured in a group of younger adults (n = 22), cognitively healthy older adults (n = 21), and patients with VCI (n = 21) using an iPad task.Results:Whereas cognitively healthy aging affected the speed (RT) of response initiation and movement but not its variability (IIV), VCI resulted in both slowed RT and increased IIV for both response phases. Furthermore, there were group differences with respect to response phase.Conclusion:These results indicate that IIV can be more sensitive than absolute RT in separating VCI from normal aging. Furthermore, compared to cognitively healthy aging, VCI was characterized by significant deficits in planning/initiating action as well as performing movements. Such deficits have important implications for real life actions such as driving safety, employment, and falls risk.

Disrupted Brain Structural Connectivity Network in Subcortical Ischemic Vascular Cognitive Impairment With No Dementia

The alteration of the functional topological organization in subcortical ischemic vascular cognitive impairment with no dementia (SIVCIND) patients has been illuminated by previous neuroimaging studies. However, in regard to the changes in the structural connectivity of brain networks, little has been reported. In this study, a total of 27 subjects, consisting of 13 SIVCIND patients, and 14 normal controls, were recruited. Each of the structural connectivity networks was constructed by diffusion tensor tractography. Subsequently, graph theory, and network-based statistics (NBS) were employed to analyze the whole-brain mean factional anisotropy matrix. After removing the factor of age, gender, and duration of formal education, the clustering coefficients (Cp) and global efficiency (Eglob) were significantly decreased and the mean path length (Lp) was significantly increased in SIVCIND patients compared with normal controls. Using the combination of four network topological parameters as the classification feature, a classification accuracy of 78% was obtained by leave-one-out cross-validation for all subjects with a sensitivity of 69% and a specificity of 86%. Moreover, we also found decreased structural connections in the SIVCIND patients, which mainly concerned fronto-occipital, fronto-subcortical, and tempo-occipital connections (NBS corrected, p < 0.01). Additionally, significantly altered nodal centralities were found in several brain regions of the SIVCIND patients, mainly located in the prefrontal, subcortical, and temporal cortices. These results suggest that cognitive impairment in SIVCIND patients is associated with disrupted topological organization and provide structural evidence for developing reliable biomarkers related to cognitive decline in SIVCIND.

Subcortical Ischemic Vascular Cognitive Impairment: Insights from Reaction Time Measures.

In this study, reaction time (RT), intraindividual variability (IIV), and errors, and the effects of practice and processing load upon such function, were compared in patients with subcortical ischemic vascular cognitive impairment (SIVCI) [n = 27] and cognitively healthy older adults (CH) [n = 26]. Compared to CH aging, SIVCI was characterized by a profile of significantly slowed RT, raised IIV, and higher error levels, particularly in the presence of distracting stimuli, indicating that the integrity and/or accessibility of the additional functions required to support high processing load, serial search strategies, are reduced in SIVCI. Furthermore, although practice speeded RT in SIVCI, unlike CH, practice did not lead to an improvement in IIV. This indicates that improvement in RT in SIVCI can in fact mask an abnormally high degree of IIV. Because IIV appears more related to disease, function, and health than RT, its status and potential for change may represent a particularly meaningful, and relevant, disease characteristic of SIVCI. Finally, a high level of within-group variation in the above measures was another characteristic of SIVCI, with such processing heterogeneity in patients with ostensibly the same diagnosis, possibly related to individual variation in pathological load. Detailed measurement of RT, IIV, errors, and practice effects therefore reveal a degree of functional impairment in brain processing not apparent by measuring RT in isolation.

Reaction Time and Visible White Matter Lesions in Subcortical Ischemic Vascular Cognitive Impairment.

Slowed behavioral reaction time is associated with pathological brain changes, including white matter lesions, the common clinical characteristic of subcortical ischemic vascular cognitive impairment (SIVCI). In the present study, reaction time (RT) employing Trails B of the Trail Making Test, with responses capped at 300 s, was investigated in SIVCI (n = 27) compared to cognitively healthy aging (CH) (n = 26). RT was significantly slowed in SIVCI compared to CH (Cohen’s d effect size = 1.26). Furthermore, failure to complete Trails B within 300 s was also a characteristic of SIVCI although some ostensibly cognitively healthy older adults also failed to complete within this time limit. Within the SIVCI group, RT did not differ significantly with respect to whether the patients were classified as having moderate/severe or mild, periventricular white matter changes visible on their diagnostic CT/MRI scans. This, together with the high degree of overlap in RT between the two SIVCI subgroups, raises the possibility that using visible ratings scales in isolation may lead to the underestimation of disease level.

THE ROLE OF S100B IN AEROBIC TRAINING EFFICACY IN OLDER ADULTS WITH MILD VASCULAR COGNITIVE IMPAIRMENT

Aerobic training improves cognitive and brain outcomes across different populations and neurocognitive disorders of aging, including mild subcortical ischemic vascular cognitive impairment (SIVCI). However, little is known of the underlying mechanisms through which aerobic training exerts its beneficial effects on the brain. Recently, S100 calcium-binding protein B (S100B) has been proposed as a possible mediator of aerobic training. At low levels, S100B is neurotrophic but at higher levels it is neurotoxic. Elevated levels of S100B have been associated with decreased performance on measures of global cognitive function. Thus, we conducted a secondary analysis of data collected from the proof-of-concept single-blind randomized controlled trial (NCT01027858) in older adults with mild SIVCI to determine whether the beneficial effects of 6-months, thrice weekly, moderate intensity aerobic training on cognitive performance is related to changes in S100B levels. In a subsample of 45 participants, blood samples were collected both before and after trial completion. Global cognitive function was assessed using Mini Mental State Examination (MMSE). At trial completion, aerobic training decreased circulating levels of S100B compared with usual care plus education (F(1,41) = 6.673, p = 0.013, ηp2 = 0.140; Figure 1). Furthermore, reduced S100B levels were associated with improved global cognitive function in those who received the aerobic exercise intervention (partial r = -0.519, p = 0.023). Together these findings suggest that S100B is a promising target mediating the beneficial effects of moderate-intensity aerobic training on brain health in older adults with mild SIVCI.

AEROBIC TRAINING, THE DEFAULT MODE NETWORK, AND COGNITION IN OLDER ADULTS WITH MILD VASCULAR COGNITIVE IMPAIRMENT

Aerobic training has been shown to be effective at improving cognitive and brain outcomes in older adults with mild subcortical ischemic vascular cognitive impairment (SIVCI). However, uncertainty remains regarding the underlying neurobiological mechanisms by which exercise elicits these improvements in cognition. Increased aberrant functional connectivity of the default mode network has been highlighted as a factor contributing to cognitive decline in older adults with cognitive impairment. Greater connectivity of the DMN at rest is associated with poorer performance on attention-demanding tasks, indicative of a lack of ability to deactivate the network on task. Our previous work on a randomized controlled trial of participants with mild SIVCI, demonstrated that 6-months of thrice weekly aerobic training led to improved global cognitive function, as measured by Alzheimer’s disease Assessment Scale-Cognitive subscale (ADAS-Cog), compared with a health education program. Thus, we conducted secondary analyses to investigate whether these changes in global cognitive function were associated with changes in resting state DMN connectivity. A subsample of 21 participants underwent a resting state functional magnetic resonance imaging (fMRI) scan before and after trial completion. Change in resting state DMN connectivity was found to significantly predict change in ADAS-Cog score (β = -.442, p=.038) after controlling for age, intervention group, and baseline functional capacity (R2=.467, F(4,16)= 3.507, p=.031). These findings suggest that functional connectivity of the DMN may underlie changes in global cognitive function. Furthermore, aerobic exercise is a promising intervention by which to elicit these changes in older adults with mild SIVCI.

The Role of S100B in Aerobic Training Efficacy in Older Adults with Mild Vascular Cognitive Impairment: Secondary Analysis of a Randomized Controlled Trial

Aerobic training improves cognitive and brain outcomes across different populations and neurocognitive disorders of aging, including mild subcortical ischemic vascular cognitive impairment (SIVCI). However, little is known of the underlying mechanisms through which aerobic training exerts its beneficial effects on the brain. Recently, S100 calcium-binding protein B (S100B) has been proposed as a possible mediator of aerobic training. Thus we conducted a secondary analysis of data collected from the proof-of-concept single-blind randomized controlled trial (NCT01027858) in older adults with mild SIVCI to determine whether the beneficial effects of 6-months, thrice weekly, moderate-intensity aerobic training on cognitive performance is related to changes in S100B levels. At trial completion, aerobic training decreased circulating levels of S100B compared with usual care plus education. Furthermore, reduced S100B levels were associated with improved global cognitive function in those who received the aerobic exercise intervention. Together these findings suggest that S100B is a promising target mediating the beneficial effects of moderate-intensity aerobic training on brain health in older adults with mild SIVCI.

Soluble Epoxide Hydrolase-Derived Linoleic Acid Oxylipins in Serum Are Associated with Periventricular White Matter Hyperintensities and Vascular Cognitive Impairment.

White matter hyperintensities (WMH) are presumed to indicate subcortical ischemic vascular disease but their underlying pathobiology remains incompletely understood. The soluble epoxide hydrolase (sEH) enzyme converts anti-inflammatory and vasoactive cytochrome p450-derived polyunsaturated fatty acid epoxides into their less active corresponding diol species. Under the hypothesis that the activity of sEH might be associated with subcortical ischemic vascular disease and vascular cognitive impairment, this study aimed to compare the relative abundance of sEH substrates and products in peripheral blood between patients with extensive WMH (discovered due to transient ischemic attack; n = 29) and healthy elderly with minimal WMH (n = 25). The concentration of 12,13-DiHOME (a sEH-derived linoleic acid metabolite), and the ratio of 12,13-DiHOME to its sEH substrate, 12,13-EpOME, were elevated in the extensive WMH group (F1,53 = 5.9, p = 0.019), as was the 9,10-DiHOME/9,10-EpOME ratio (F1,53 = 5.4, p = 0.024). The 12,13-DiHOME/12,13-EpOME ratio was associated with poorer performance on a composite score derived from tests of psychomotor processing speed, attention, and executive function (β = - 0.473, p = 0.001, adjusted r2 = 0.213), but not with a composite verbal memory score. In a mediation model, periventricular WMH (but not deep WMH), explained 37% of the effect of the 12,13-DiHOME/12,13-EpOME ratio on the speed/attention/executive function composite score (indirect effect = - 0.50, 95% bootstrap confidence interval [- 0.99, - 0.17] Z-score units). Serum oxylipin changes consistent with higher sEH activity were markers of vascular cognitive impairment, and this association was partly explained by injury to the periventricular subcortical white matter.

Increased Aerobic Fitness Is Associated with Cortical Thickness in Older Adults with Mild Vascular Cognitive Impairment

Vascular cognitive impairment (VCI) results from cerebrovascular disease and is the second most common type of cognitive dysfunction. Sub-cortical ischemic vascular cognitive impairment (SIVCI) is the most common form of VCI. Current evidence suggests that increased or maintained cortical thickness might be one mechanism by which aerobic exercise preserves cognitive function in older adults. Whether this is also a potential pathway among older adults with SIVCI is unknown. Therefore, the aim of this secondary analysis of a 6-month proof-of-concept single-blinded randomized controlled trial of aerobic exercise was to investigate the associations between (1) aerobic-induced improvements in aerobic fitness capacity and change in cortical thickness in older adults with mild SIVCI; and (2) change in cortical thickness and changes in executive functions. This is a secondary analysis of neuroimaging data from a randomized controlled trial with 71 older adults with SIVCI who were randomly assigned to either a 6-month thrice-weekly aerobic training program or a 6-month nutrition program (i.e., control). Outcome measures were assessed at baseline and trial completion (i.e., 6 months). Aerobic fitness capacity was assessed with the 6-min walk test (6MWT). Magnetic resonance imaging data were acquired at both measurement points from 28 participants to look at changes in cortical thickness. Executive functions were assessed using (1) the Stroop test, (2) the trail making test (part A&B), and (3) the digit symbol substitution test (DSST). At trial completion, compared with the control group, participants in the aerobic training group showed significantly improved 6MWT performance (p = .037). Improved 6MWT performance was independently and significantly associated with increased change in cortical thickness, after controlling for baseline cortical thickness, baseline age, and baseline MoCA (p = .045). Specifically, change in 6MWT performance was significantly positively associated with change in the right superior temporal gyrus thickness (r = .557, p = .002). Maintenance of cortical thickness was independently and significantly associated with improved processing speed performance on the DSST over the 6-month trial, after controlling for baseline DSST performance, baseline age, and baseline MoCA (p = .014). Specifically, change in DSST performance was significantly positively associated with change in the right superior frontal thickness (r = .595, p = .002). Thus, a 6-month aerobic training program may promote cognitive outcomes in older adults with mild SIVCI by improving aerobic fitness capacity and maintaining cortical thickness.

Progressively Disrupted Brain Functional Connectivity Network in Subcortical Ischemic Vascular Cognitive Impairment Patients.

Cognitive impairment caused by subcortical ischemic vascular disease (SIVD) has been elucidated by many neuroimaging studies. However, little is known regarding the changes in brain functional connectivity networks in relation to the severity of cognitive impairment in SIVD. In the present study, 20 subcortical ischemic vascular cognitive impairment no dementia patients (SIVCIND) and 20 dementia patients (SIVaD) were enrolled; additionally, 19 normal controls were recruited. Each participant underwent a resting-state functional MRI scan. Whole-brain functional networks were analyzed with graph theory and network-based statistics (NBS) to study the functional organization of networks and find alterations in functional connectivity among brain regions. After adjustments for age, gender, and duration of formal education, there were significant group differences for two network functional organization indices, global efficiency and local efficiency, which decreased (NC > SIVCIND > SIVaD) as cognitive impairment worsened. Between-group differences in functional connectivity (NBS corrected, p < 0.01) mainly involved the orbitofrontal, parietal, and temporal cortices, as well as the basal ganglia. The brain connectivity network was progressively disrupted as cognitive impairment worsened, with an increased number of decreased connections between brain regions. We also observed more reductions in nodal efficiency in the prefrontal and temporal cortices for SIVaD than for SIVCIND. These findings indicated a progressively disrupted pattern of the brain functional connectivity network with increased cognitive impairment and showed promise for the development of reliable biomarkers of network metric changes related to cognitive impairment caused by SIVD.

Sex Difference in Aerobic Exercise Efficacy to Improve Cognition in Older Adults with Vascular Cognitive Impairment: Secondary Analysis of a Randomized Controlled Trial

Aerobic training (AT) is a promising, non-pharmacological intervention to mitigate the deleterious effects of aging and disease on brain health. However, a large amount of variation exists in its efficacy. This is a secondary analysis of a randomized controlled trial of AT in 71 older adults with subcortical ischemic vascular cognitive impairment (NCT01027858). Specifically, we investigated: 1) whether sex moderates the relationship between AT and executive functions, and 2) the role of brain derived neurotrophic factor (BDNF) and gains in functional fitness capacity. Older adults were randomly assigned to either 6-month, thrice-weekly AT or to usual care plus education (CON). At baseline, trial completion, and 6-month follow-up, executive functions were assessed with the Trail Making Test (A & B), verbal digits forward and backward test, and the Stroop Test. Functional fitness capacity was assessed with the 6-Minute Walk Test. Compared with CON, AT significantly improved Trail Making Test performance in females but not males, an effect that was retained at follow-up. AT significantly increased BDNF levels in females but decreased levels in males. On the other hand, AT led to significant gains in functional fitness capacity in males only. This study provides evidence that sex differences exist in AT efficacy on brain health as well as in the biological mechanisms subserving AT.

The role of exercise in mitigating subcortical ischemic vascular cognitive impairment.

Subcortical ischemic vascular cognitive impairment (SIVCI) is the most preventable form of cognitive dysfunction. There is converging evidence from animal and human studies that indicate vascular injury as the primary cause of SIVCI. Currently, there are no curative pharmaceutical treatments for vascular dementia; however, exercise may be a promising strategy to combat SIVCI. This review will focus on the role of exercise as a strategy to prevent or slow the progression of SIVCI, with particular emphasis on the mechanisms by which exercise may improve cerebrovascular function. We propose that exercise may be an effective strategy to combat SIVCI by improving cognitive function, increasing the bioavailability of neurotrophins, stimulating endothelial function, and controlling vascular risk factors. This article is part of the Special Issue "Vascular Dementia".

The Impact of Aerobic Exercise on Fronto-Parietal Network Connectivity and Its Relation to Mobility: An Exploratory Analysis of a 6-Month Randomized Controlled Trial.

Impaired mobility is a major concern for older adults and has significant consequences. While the widely accepted belief is that improved physical function underlies the effectiveness of targeted exercise training in improving mobility and reducing falls, recent evidence suggests cognitive and neural benefits gained through exercise may also play an important role in promoting mobility. However, the underlying neural mechanisms of this relationship are currently unclear. Thus, we hypothesize that 6 months of progressive aerobic exercise training would alter frontoparietal network (FPN) connectivity during a motor task among older adults with mild subcortical ischemic vascular cognitive impairment (SIVCI)—and exercise-induced changes in FPN connectivity would correlate with changes in mobility. We focused on the FPN as it is involved in top-down attentional control as well as motor planning and motor execution. Participants were randomized either to usual-care (CON), which included monthly educational materials about VCI and healthy diet; or thrice-weekly aerobic training (AT), which was walking outdoors with progressive intensity. Functional magnetic resonance imaging was acquired at baseline and trial completion, where the participants were instructed to perform bilateral finger tapping task. At trial completion, compared with AT, CON showed significantly increased FPN connectivity strength during right finger tapping (p < 0.05). Across the participants, reduced FPN connectivity was associated with greater cardiovascular capacity (p = 0.05). In the AT group, reduced FPN connectivity was significantly associated with improved mobility performance, as measured by the Timed-Up-and-Go test (r = 0.67, p = 0.02). These results suggest progressive AT may improve mobility in older adults with SIVCI via maintaining intra-network connectivity of the FPN.