Exercise effects on brain health and learning from minutes to months: The brain EXTEND trial.

Despite evidence that aerobic exercise benefits the aging brain, in particular the hippocampus and memory, controlled clinical trials have not comprehensively evaluated effects of aerobic exercise training on human memory in older adults. The central goal of this study was to determine chronic effects of moderate-to-vigorous intensity aerobic exercise on the hippocampus and memory in non-demented, inactive adults ages 55-80 years. We determine effects of aerobic exercise training with a 6-month randomized controlled trial (RCT) comparing 150 min/week of home-based, light intensity exercise with progressive moderate-to-vigorous intensity aerobic exercise. For the first time in a large trial, we examined temporal mechanisms by determining if individual differences in the rapid, immediate effects of moderate intensity exercise on hippocampal-cortical connectivity predict chronic training-related changes over months in connectivity and memory. We examined physiological mechanisms by testing the extent to which chronic training-related changes in cardiorespiratory fitness are a critical factor to memory benefits. The Exercise Effects on Brain Connectivity and Learning from Minutes to Months (Brain-EXTEND) trial is conceptually innovative with advanced measures of hippocampal-dependent learning and memory processes combined with novel capture of the physiological changes, genetic components, and molecular changes induced by aerobic exercise that change hippocampal-cortical connectivity. Given that hippocampal connectivity deteriorates with Alzheimer's and aerobic exercise may contribute to reduced risk of Alzheimer's, our results could lead to an understanding of the physiological mechanisms and moderators by which aerobic exercise reduces risk of this devastating and costly disease.

Age-related differences in resting-state, task-related, and structural brain connectivity: graph theoretical analyses and visual search performance.

Previous magnetic resonance imaging (MRI) research suggests that aging is associated with a decrease in the functional interconnections within and between groups of locally organized brain regions (modules). Further, this age-related decrease in the segregation of modules appears to be more pronounced for a task, relative to a resting state, reflecting the integration of functional modules and attentional allocation necessary to support task performance. Here, using graph-theoretical analyses, we investigated age-related differences in a whole-brain measure of module connectivity, system segregation, for 68 healthy, community-dwelling individuals 18-78 years of age. We obtained resting-state, task-related (visual search), and structural (diffusion-weighted) MRI data. Using a parcellation of modules derived from the participants' resting-state functional MRI data, we demonstrated that the decrease in system segregation from rest to task (i.e., reconfiguration) increased with age, suggesting an age-related increase in the integration of modules required by the attentional demands of visual search. Structural system segregation increased with age, reflecting weaker connectivity both within and between modules. Functional and structural system segregation had qualitatively different influences on age-related decline in visual search performance. Functional system segregation (and reconfiguration) influenced age-related decline in the rate of visual evidence accumulation (drift rate), whereas structural system segregation contributed to age-related slowing of encoding and response processes (nondecision time). The age-related differences in the functional system segregation measures, however, were relatively independent of those associated with structural connectivity.

The association of structural versus load-dependent large artery stiffness mechanisms with cerebrovascular damage and cortical atrophy in humans.

Large central arterial stiffness is a risk factor for cerebrovascular damage and subsequent progression of neurodegenerative diseases, including Alzheimer's disease and dementia. However, arterial stiffness is determined by both the intrinsic components of the arterial wall (structural stiffness) and the load (i.e., arterial blood pressure) exerted upon it by the blood (load-dependent stiffness). This study aimed to determine the degree to which structural and/or load-dependent mechanisms of central arterial stiffness are associated with cerebrovascular damage. Among 128 healthy individuals (aged 63±6, age range: 50-80 years, 42% men), aortic and carotid artery stiffness was measured via carotid-femoral pulse wave velocity and B-mode ultrasonography, respectively. Using participant-specific exponential models, both aortic and carotid artery stiffness were standardized to a reference blood pressure to separate their structural and load-dependent stiffness mechanisms. Magnetic resonance imaging was used to derive total, periventricular, and deep cerebral white matter lesion volume (WMLV) and global cortical thickness. After adjusting for common cardiovascular disease risk factors, a 1 m/s increase in structural aortic stiffness was associated with 15% greater total WMLV (95% confidence interval [CI] = 0.01, 0.27, P = 0.036), 14% greater periventricular WMLV (95%CI = 0.004, 0.25, P = 0.044) and 0.011mm lower cortical thickness (95%CI = -0.022, -1.18, P = 0.028). No association was observed between structural carotid stiffness and WMLVs (total, periventricular, and deep), and neither aortic nor carotid load-dependent stiffness was associated with WMLVs or cortical thickness. Structural, not load-dependent, mechanisms of aortic stiffness are related to cerebrovascular-related white matter damage.

Pre-operative anaemia-does it influence post-operative outcomes after isolated coronary artery bypass grafting?

Introduction: Preoperative anaemia is prevalent in a number of patients undergoing coronary artery bypass grafting. Studies provide conflicting results due to several reasons including variation in the threshold of haematocrit used to define anaemia. We aimed to assess the independent effect of preoperative anaemia on outcomes in patients undergoing off pump coronary artery bypass grafting (OPCAB). Methods: In this retrospective study, patients with a hemoglobin level less than 11g/dl (haematocrit <33%) were considered to have moderate-to-severe anaemia as per the recommendations of the World Health Organization. Association between haematocrit <33% and mortality as well as adverse post-operative outcomes was assessed. Multivariable logistic regression (MLR) was carried out to assess the independent effect of haematocrit<33% on 30-day mortality and other outcomes. Results: The study included 4957 consecutive patients undergoing isolated OPCAB surgery between 2015 and 2020. Out of 4957, 635 (12.8%) had haematocrit <33% and 4322 (81.2%) had haematocrit ≥33%. Patients with haematocrit < 33% had a 30-day mortality of 13 (2%) compared to 38 (0.9%) in patients without anaemia and had a greater requirement for blood transfusion (p<0.0001). It was also associated with an increased incidence of renal failure (p<0.0001), tracheostomy (p=.0.012) and risk of re-intubation (p=0.006). On multiple linear regression (MLR), haematocrit < 33% was not an independent predictor of 30-day mortality odds ratio (OR) 1.47, 95% confidence interval (CI) 0.745-2.917; p=0.26. It was however an important independent risk factor for blood transfusion (OR 1.80, 95% CI 1.29-2.50, p<0.001) and renal failure (OR 3.06, 95% CI 1.338-7.012, p=0.008). The receiver operating characteristic (ROC)-area under the curve (AUC) was 0.63 suggesting moderate discriminatory value of haematocrit < 33% for 30-day mortality. Conclusion: Haematocrit < 33% is an important risk factor for adverse outcomes following isolated, primary, elective OPCAB. Supplementary Information: The online version contains supplementary material available at 10.1007/s12055-024-01746-1.

Physical Performance and Amyloid-ß in Humans: A Systematic Review and Meta-Analysis of Observational Studies.

BACKGROUND: Accumulation of amyloid-ß (Aß) plaques is one of the main features of Alzheimer's disease (AD). Physical performance has been related to dementia risk and Aß, and it has been hypothesized as one of the mechanisms leading to greater accumulation of Aß. Yet, no evidence synthesis has been performed in humans. OBJECTIVE: To investigate the association of physical performance with Aß in humans, including Aß accumulation on brain, and Aß abnormalities measured in cerebrospinal fluid (CSF) and blood. METHODS: A systematic review with multilevel meta-analysis was performed from inception to June 16th, 2022. Studies were eligible if they examined the association of physical performance with Aß levels, including the measure of physical performance as a predictor and the measure of Aß as an outcome in humans. RESULTS: 7 articles including 2,619 participants were included in the meta-analysis. The results showed that physical performance was not associated with accumulation of Aß in the brain (ES = 0.01; 95% CI -0.21 to 0.24; I2 = 69.9%), in the CSF (ES = -0.28; 95% CI -0.98 to 0.41; I2 = 91.0%) or in the blood (ES = -0.19; 95% CI -0.61 to 0.24; I2 = 99.75%). Significant heterogeneity was found across the results , which posed challenges in arriving at consistent conclusions; and the limited number of studies hindered the opportunity to conduct a moderation analysis. CONCLUSIONS: The association between physical performance and Aß is inconclusive. This uncertainly arises from the limited number of studies, study design limitations, and heterogeneity of measurement approaches. More studies are needed to determine whether physical performance is related to Aß levels in humans.

Functional connectivity of the cerebellar vermis in bipolar disorder and associations with mood.

Purpose: Studies of the neural underpinnings of bipolar type I disorder have focused on the emotional control network. However, there is also growing evidence for cerebellar involvement, including abnormal structure, function, and metabolism. Here, we sought to assess functional connectivity of the cerebellar vermis with the cerebrum in bipolar disorder and to assess whether connectivity might depend on mood. Methods: This cross-sectional study enrolled 128 participants with bipolar type I disorder and 83 control comparison participants who completed a 3 T magnetic resonance imaging (MRI) study, which included anatomical as well as resting state Blood Oxygenation Level Dependent (BOLD) imaging. Functional connectivity of the cerebellar vermis to all other brain regions was assessed. Based on quality control metrics of the fMRI data, 109 participants with bipolar disorder and 79 controls were included in the statistical analysis comparing connectivity of the vermis. In addition, the data was explored for the potential impacts of mood, symptom burden, and medication in those with bipolar disorder. Results: Functional connectivity between the cerebellar vermis and the cerebrum was found to be aberrant in bipolar disorder. The connectivity of the vermis was found to be greater in bipolar disorder to regions involved in motor control and emotion (trending), while reduced connectivity was observed to a region associated with language production. In the participants with bipolar disorder, past depression symptom burden affected connectivity; however, no effects of medication were observed. Functional connectivity between the cerebellar vermis and all other regions revealed an inverse association with current mood ratings. Conclusion: Together the findings may suggest that the cerebellum plays a compensatory role in bipolar disorder. The proximity of the cerebellar vermis to the skull may make this region a potential target for treatment with transcranial magnetic stimulation.

Functional Connectivity of the Cerebellar Vermis in Bipolar Disorder and Associations with Mood.

Purpose: Studies of the neural underpinnings of bipolar type I disorder have focused on the emotional control network. However, there is also growing evidence for cerebellar involvement, including abnormal structure, function, and metabolism. Here, we sought to assess functional connectivity of the cerebellum with the cerebrum in bipolar disorder and to assess whether any effects might depend on mood. Methods: This cross-sectional study enrolled 128 participants with bipolar type I disorder and 83 control comparison participants who completed a 3T MRI scan, which included anatomical imaging as well as resting state BOLD imaging. Functional connectivity of the cerebellar vermis to all other brain regions was assessed. Based on quality control metrics of the fMRI data, 109 participants with bipolar disorder and 79 controls were used to in the statistical analysis comparing connectivity of the vermis as well as associations with mood. Potential impacts of medications were also explored. Results: Functional connectivity of the cerebellar vermis in bipolar disorder was found to differ significantly between brain regions known to be involved in the control of emotion, motor function, and language. While connections with emotion and motor control areas were significantly stronger in bipolar disorder, connection to a region associated language production was significantly weaker. In the participants with bipolar disorder, ratings of depression and mania were inversely associated with vermis functional connectivity. No effect of medications on these connections were observed. Conclusion: Together the findings suggest cerebellum may play a compensatory role in bipolar disorder and when it can no longer fulfill this role, depression and mania develop. The proximity of the cerebellar vermis to the skull may make this region a potential target for treatment with transcranial magnetic stimulation.

Getting Fit to Counteract Cognitive Aging: Evidence and Future Directions.

Physical activity has shown tremendous promise for counteracting cognitive aging, but also tremendous variability in cognitive benefits. We describe evidence for how exercise affects cognitive and brain aging, and whether cardiorespiratory fitness is a key factor. We highlight a brain network framework as a valuable paradigm for the mechanistic insight needed to tailor physical activity for cognitive benefits.

Cortical iron mediates age-related decline in fluid cognition.

Brain iron dyshomeostasis disrupts various critical cellular functions, and age-related iron accumulation may contribute to deficient neurotransmission and cell death. While recent studies have linked excessive brain iron to cognitive function in the context of neurodegenerative disease, little is known regarding the role of brain iron accumulation in cognitive aging in healthy adults. Further, previous studies have focused primarily on deep gray matter regions, where the level of iron deposition is highest. However, recent evidence suggests that cortical iron may also contribute to cognitive deficit and neurodegenerative disease. Here, we used quantitative susceptibility mapping (QSM) to measure brain iron in 67 healthy participants 18-78 years of age. Speed-dependent (fluid) cognition was assessed from a battery of 12 psychometric and computer-based tests. From voxelwise QSM analyses, we found that QSM susceptibility values were negatively associated with fluid cognition in the right inferior temporal gyrus, bilateral putamen, posterior cingulate gyrus, motor, and premotor cortices. Mediation analysis indicated that susceptibility in the right inferior temporal gyrus was a significant mediator of the relation between age and fluid cognition, and similar effects were evident for the left inferior temporal gyrus at a lower statistical threshold. Additionally, age and right inferior temporal gyrus susceptibility interacted to predict fluid cognition, such that brain iron was negatively associated with a cognitive decline for adults over 45 years of age. These findings suggest that iron may have a mediating role in cognitive decline and may be an early biomarker of neurodegenerative disease.

Influence of structural and functional brain connectivity on age-related differences in fluid cognition.

We used graph theoretical measures to investigate the hypothesis that structural brain connectivity constrains the influence of functional connectivity on the relation between age and fluid cognition. Across 143 healthy, community-dwelling adults 19-79 years of age, we estimated structural network properties from diffusion-weighted imaging and functional network properties from resting-state functional magnetic resonance imaging. We confirmed previous reports of age-related decline in the strength and efficiency of structural networks, as well as in the connectivity strength within and between structural network modules. Functional networks, in contrast, exhibited age-related decline only in system segregation, a measure of the distinctiveness among network modules. Aging was associated with decline in a composite measure of fluid cognition, particularly tests of executive function. Functional system segregation was a significant mediator of age-related decline in executive function. Structural network properties did not directly influence the age-related decline in functional system segregation. The raw correlational data underlying the graph theoretical measures indicated that structural connectivity exerts a limited constraint on age-related decline in functional connectivity.

Neural activation for actual and imagined movement following unilateral hand transplantation: a case study.

Transplantation of a donor hand has been successful as a surgical treatment following amputation, but little is known regarding the brain mechanisms contributing to the recovery of motor function. We report functional magnetic resonance imaging (fMRI) findings for neural activation related to actual and imagined movement, for a 54-year-old male patient, who had received a donor hand transplant 50 years following amputation. Two assessments, conducted 3 months and 6 months post-operatively, demonstrate engagement of motor-control related brain regions for the transplanted hand, during both actual and imagined movement of the fingers. The intact hand exhibited a more intense and focused pattern of activation for actual movement relative to imagined movement, whereas activation for the transplanted hand was more widely distributed and did not clearly differentiate actual and imagined movement. However, the spatial overlap of actual-movement and imagined-movement voxels, for the transplanted hand, did increase over time to a level comparable to that of the intact hand. At these relatively early post-operative assessments, brain regions outside of the canonical motor-control networks appear to be supporting movement of the transplanted hand.

The ties to unbind: age-related differences in feature (un)binding in working memory for emotional faces.

In the present study, we investigated age-related differences in the processing of emotional stimuli. Specifically, we were interested in whether older adults would show deficits in unbinding emotional expression (i.e., either no emotion, happiness, anger, or disgust) from bound stimuli (i.e., photographs of faces expressing these emotions), as a hyper-binding account of age-related differences in working memory would predict. Younger and older adults completed different N-Back tasks (side-by-side 0-Back, 1-Back, 2-Back) under three conditions: match/mismatch judgments based on either the identity of the face (identity condition), the face's emotional expression (expression condition), or both identity and expression of the face (both condition). The two age groups performed more slowly and with lower accuracy in the expression condition than in the both condition, indicating the presence of an unbinding process. This unbinding effect was more pronounced in older adults than in younger adults, but only in the 2-Back task. Thus, older adults seemed to have a specific deficit in unbinding in working memory. Additionally, no age-related differences were found in accuracy in the 0-Back task, but such differences emerged in the 1-Back task, and were further magnified in the 2-Back task, indicating independent age-related differences in attention/STM and working memory. Pupil dilation data confirmed that the attention/STM version of the task (1-Back) is more effortful for older adults than younger adults.