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Behavioral interventions have shown promising neuroprotective effects, but the cascade of molecular, brain and behavioral changes involved in these benefits remains poorly understood. Projecte Moviment is a 12-week (5 days per week – 45 min per day) multi-domain, single-blind, proof-of-concept randomized controlled trial examining the cognitive effect and underlying mechanisms of an aerobic exercise (AE), computerized cognitive training (CCT) and a combined (COMB) groups compared to a waitlist control group. Adherence was >80% for 82/109 participants recruited (62% female; age = 58.38 ± 5.47). In this study we report intervention-related changes in plasma biomarkers (BDNF, TNF-α, HGF, ICAM-1, SDF1-α) and structural-MRI (brain volume) and how they related to changes in physical activity and individual variables (age and sex) and their potential role as mediators in the cognitive changes. Our results show that although there were no significant changes in molecular biomarker concentrations in any intervention group, changes in ICAM-1 and SDF1-α were negatively associated with changes in physical activity outcomes in AE and COMB groups. Brain volume changes were found in the CCT showing a significant increase in precuneus volume. Sex moderated the brain volume change in the AE and COMB groups. Changes in molecular biomarkers and brain volumes did not significantly mediate the cognitive-related benefits found previously for any group. This study shows crucial initial molecular and brain volume changes related to lifestyle interventions at early stages and highlights the value of examining activity parameters, individual difference characteristics and using a multi-level analysis approach to address these questions.

Lifestyle interventions are promising strategies to promote cognitive health in aging. Projecte Moviment examines if aerobic exercise (AE), computerized cognitive training (CCT), and their combination (COMB) improves cognition, psychological health, and physical status compared to a control group. We assessed the moderating role of age and sex and the mediating effects of cardiorespiratory fitness (CRF), physical activity (PA), and psychological health on intervention-related cognitive benefits. This was a 12-week multi-domain, single-blind, proof-of-concept randomized controlled trial (RCT). 96 healthy adults aged 50-70 years were assigned to AE, CCT, COMB, and a wait-list control group. The per protocol sample, which completed the intervention with a level of adherence > 80%, consisted of 82 participants (62% female; age = 58.38 ± 5.47). We assessed cognition, psychological health, CRF, and energy expenditure in PA at baseline and after the intervention. We regressed change in each outcome on the treatment variables, baseline score, sex, age, and education. We used PROCESS Macro to perform the mediation and moderation analyses. AE benefited Working Memory (SMD = 0.29, = 0.037) and Attention (SMD = 0.33, = 0.028) including the Attention-Speed (SMD = 0.31, = 0.042) domain, compared to Control. COMB improved Attention (SMD = 0.30, = 0.043), Speed (SMD = 0.30, = 0.044), and the Attention-Speed (SMD = 0.30, = 0.041) domain. CTT group did not show any cognitive change compared to Control. Sportive PA (S-PA) and CRF increased in AE and COMB. Age and sex did not moderate intervention-related cognitive benefits. Change in S-PA, but not in CRF, significantly mediated improvements on Attention-Speed in AE. A 12-week AE program improved Executive Function and Attention-Speed in healthy late-middle-aged adults. Combining it with CCT did not provide further benefits. Our results add support to the clinical relevance of even short-term AE as an intervention to enhance cognition and highlight the mediating role of change in S-PA in these benefits. www.ClinicalTrials.gov, identifier NCT03123900.

Cerebral white matter lesions (WMLs) have been consistently related to cognitive dysfunction but the role of white matter (WM) damage in cognitive impairment is not fully determined. Diffusion tensor imaging is a promising tool to explain impaired cognition related to WMLs. We investigated the separate association of high-grade periventricular hyperintensities (PVHs) and deep white matter hyperintensities (DWMHs) with fractional anisotropy (FA) in middle-aged individuals. We also assessed the predictive value to cognition of FA within specific WM tracts associated with high-grade WMLs. One hundred participants from the Barcelona-AsIA Neuropsychology Study were divided into groups based on low- and high-grade WMLs. Voxel-by-voxel FA were compared between groups, with separate analyses for high-grade PVHs and DWMHs. The mean FA within areas showing differences between groups was extracted in each tract for linear regression analyses. Participants with high-grade PVHs and participants with high-grade DWMHs showed lower FA in different areas of specific tracts. Areas showing decreased FA in high-grade DWMHs predicted lower cognition, whereas areas with decreased FA in high-grade PVHs did not. The predictive value to cognition of specific WM tracts supports the involvement of cortico-subcortical circuits in cognitive deficits only in DWMHs.

Background/Objectives: Stroke often leads to persistent cognitive and emotional impairments, which rehabilitation may mitigate. However, the biological mechanisms underlying such improvements remain unclear. This study investigated whether supplementing computerized cognitive training (CCT) with mindfulness-based stress reduction (MBSR) or physical exercise (PE) modulated biomarkers of neuroplasticity, inflammation, and stress in patients with chronic stroke compared to CCT alone. We also explored whether biomarker changes mediated or correlated with behavioral improvements. Methods: In a three-arm, single-blind, randomized controlled trial (NCT04759950), 141 patients with chronic stroke were randomized (1:1:1) to MBSR+CCT, PE+CCT, or CCT-only for 12 weeks. Plasma levels of brain-derived neurotrophic factor (BDNF), insulin-like growth factor-1 (IGF-1), vascular endothelial growth factor (VEGF), C-reactive protein (CRP), interleukin-6 (IL-6), and cortisol were measured at baseline and post-intervention. Cognitive, mental health, mindfulness, and fitness outcomes were also assessed. Between- and within-group changes were analyzed using ANCOVA and paired t-tests. Per-protocol and complete-case analyses were conducted. Results: Among the 109 participants with ≥80% adherence, the only significant between-group difference was for VEGF: it remained stable in the MBSR+CCT group but declined in PE+CCT and CCT-only. Within-group analyses showed significant decreases in cortisol in MBSR+CCT and PE+CCT, while IGF-1 levels declined across all groups. In contrast, BDNF, IL-6, and CRP did not show significant changes, and biomarker changes were not significantly associated with behavioral improvements. Complete-case analysis (n = 126) yielded similar findings. Conclusions: Our findings suggest that combining MBSR or PE with CCT may modulate certain biological processes relevant to stroke recovery. MBSR may help maintain VEGF levels, which could support vascular health, while MBSR and PE may contribute to lowering cortisol levels. However, since no clear association with behavioral improvements was found, further research is needed to determine the clinical relevance of these biomarker changes in stroke recovery.

Cognitive aging trajectories differ widely across individuals, and genetic factors such as APOE and BDNF polymorphisms may contribute to this variability. While APOE ε4 has been widely studied, the influence of APOE ε2, particularly in interaction with sex, remains underexplored. This study aims to examine the longitudinal trajectory of APOE ε2 individuals on cognitive performance, and their interactions with sex, age, and BDNF Val66Met polymorphism, in a population-based cohort of older adults with vascular risk. We analyzed data from 386 participants (mean age: 71.8) from the Barcelona-AsIA Neuropsychology Study, followed over a 7-year period. Verbal memory, verbal fluency, and visuospatial domains were assessed. Linear regression models tested associations between cognitive change and genotypes, controlling for age, sex, education, depression, and vascular risk. Interaction terms and permutation testing were applied. Regression to the mean (RTM) effects were assessed. BDNF showed no significant associations with cognitive performance. RTM effects were evident across subgroups, particularly among ε2 carriers, suggesting this phenomenon partly explains the divergent results over time. APOE ε2 does not confer a consistent protective effect on cognition over time. Our results highlight that APOE ε2 may be detrimental to verbal memory in aging males.

The association of cerebral white matter lesions (WMLs) with cognitive status is not well understood in middle-aged individuals. Our aim was to determine the specific contribution of periventricular hyperintensities (PVHs) and deep white matter hyperintensities (DWMHs) to cognitive function in a community sample of asymptomatic participants aged 50 to 65 years. One hundred stroke- and dementia-free adults completed a comprehensive neuropsychological battery and brain MRI protocol. Participants were classified according to PVH and DWMH scores (Fazekas scale). We dichotomized our sample into low grade WMLs (participants without or with mild lesions) and high grade WMLs (participants with moderate or severe lesions). Analyses were performed separately in PVH and DWMH groups. High grade DWMHs were associated with significantly lower scores in executive functioning (−0.45 standard deviations [SD]), attention (−0.42 SD), verbal fluency (−0.68 SD), visual memory (−0.52 SD), visuospatial skills (−0.79 SD), and psychomotor speed (−0.46 SD). Further analyses revealed that high grade DWMHs were also associated with a three- to fourfold increased risk of impaired scores (i.e.,<1.5 SD) in executive functioning, verbal fluency, visuospatial skills, and psychomotor speed. Our findings suggest that only DWMHs, not PVHs, are related to diminished cognitive function in middle-aged individuals. (JINS, 2012, 18, 1–12)

Background: Risk factors for vascular cognitive impairment (VCI) are the same as traditional risk factors for cerebrovascular disease (CVD). Early identification of subjects at higher risk of VCI is important for the development of effective preventive strategies. In addition to traditional vascular risk factors (VRF), circulating biomarkers have emerged as potential tools for early diagnoses, as they could provide in vivo measures of the underlying pathophysiology. While VRF have been consistently linked to a VCI profile (i.e., deficits in executive functions and processing speed), the cognitive correlates of CVD biomarkers remain unclear. In this population-based study, the aim was to study and compare cognitive patterns in relation to VRF and circulating biomarkers of CVD. Methods: The Barcelona-AsIA Neuropsychology Study included 747 subjects older than 50, without a prior history of stroke or coronary disease and with a moderate to high vascular risk (mean age, 66 years; 34.1% women). Three cognitive domains were derived from factoral analysis: visuospatial skills/speed, verbal memory and verbal fluency. Multiple linear regression was used to assess relationships between cognitive performance (multiple domains) and a panel of circulating biomarkers, including indicators of inflammation, C-reactive protein (CRP) and resistin, endothelial dysfunction, asymmetric dimethylarginine (ADMA), thrombosis, plasminogen activator inhibitor 1 (PAI-1), as well as traditional VRF, metabolic syndrome and insulin resistance (homeostatic model assessment for insulin resistance index). Analyses were adjusted for age, gender, years of education and depressive symptoms. Results: Traditional VRF were related to lower performance in verbal fluency, insulin resistance accounted for lower performance in visuospatial skills/speed and the metabolic syndrome predicted lower performance in both cognitive domains. From the biomarkers of CVD, CRP was negatively related to verbal fluency performance and increasing ADMA levels were associated with lower performance in verbal memory. Resistin and PAI-1 did not relate to cognitive function performance. Conclusion: Vascular risk factors, and markers of inflammation and endothelial dysfunction predicted lower performance in several cognitive domains. Specifically, cognitive functions associated with CRP are typically affected in VCI and overlap those related to VRF. ADMA indicated a dissociation in the cognitive profile involving verbal memory. These findings suggest that inflammation and endothelial dysfunction might play a role in the predementia cognitive impairment stages.

Background: The contribution of traditional vascular risk factors to cognitive impairment and dementia is well known. However, in order to obtain possible targets for prevention of vascular cognitive impairment (VCI), it may be important to identify other early and noninvasive markers in asymptomatic middle-aged adults. The calculation of middle cerebral artery-pulsatility index (MCA-PI) is an ultrasonologic, noninvasive, validated and easily reproducible technique to assess increased distal resistance to blood flow. This study aims to assess the relationship between MCA-PI, microstructural white matter (WM) integrity and cognition in a middle-aged asymptomatic population. Methods: Ninety-five participants from the Barcelona-Asymptomatic Intracranial Atherosclerosis (AsIA) neuropsychology study were included. Subjects were 50-65 years old, free from dementia and without history of vascular disease. Transcranial color-coded duplex ultrasound examination was performed to assess MCA-PI as a measure of vascular resistance. WM integrity was evaluated by fractional anisotropy (FA) measurements of diffusion tensor images (DTI) acquired on a 3T-MRI. The neuropsychological battery was specifically selected to be sensitive to VCI, and included tests that were grouped into six cognitive domains: executive functioning, attention, verbal fluency, memory, visuospatial skills and psychomotor speed. A multivariate linear regression model adjusted for age, gender, years of education, diabetes and hypertension was performed. Results: MCA-PI was significantly associated with WM disintegration in different tracts (fornix, corticospinal and anterior thalamic), all p < 0.05 uncorrected. Both mean MCA-PI and mean FA of those significant tracts were independently associated with poor performance in attention, psychomotor speed, and visuospatial skills after adjustment for age, gender, years of education, and vascular risk factors (all p < 0.05). MCA-PI was independently associated with lower scores in all cognitive domains, except for visuospatial skills. Conclusions: Our data suggest that MCA-PI may be related to WM disintegration and early vascular cognitive impairment in middle-aged subjects. Although further prospective studies are needed to provide evidence for its validity in longitudinal studies, our results support the proposal of including MCA-PI as part of clinical assessment in order to identify targets for VCI prevention.