AT(N) biomarker profiles and Alzheimer's disease symptomology in Down syndrome.

INTRODUCTION: Down syndrome (DS) is a genetic cause of early-onset Alzheimer's disease (AD). The National Institute on Aging-Alzheimer's Association AT(N) Research Framework is a staging model for AD biomarkers but has not been assessed in DS. METHOD: Data are from the Alzheimer's Biomarker Consortium-Down Syndrome. Positron emission tomography (PET) amyloid beta (Aß; 15 mCi of [11 C]Pittsburgh compound B) and tau (10 mCi of [18 F]AV-1451) were used to classify amyloid (A) -/+ and tau (T) +/-. Hippocampal volume classified neurodegeneration (N) -/+. The modified Cued Recall Test assessed episodic memory. RESULTS: Analyses included 162 adults with DS (aged M = 38.84 years, standard deviation = 8.41). Overall, 69.8% of participants were classified as A-/T-/(N)-, 11.1% were A+/T-/(N)-, 5.6% were A+/T+/(N)-, and 9.3% were A+/T+/(N)+. Participants deemed cognitively stable were most likely to be A-T-(N)- and A+T-(N)-. Tau PET (T+) most closely aligning with memory impairment and AD clinical status. DISCUSSION: Findings add to understanding of AT(N) biomarker profiles in DS. HIGHLIGHTS: Overall, 69.8% of adults with Down syndrome (DS) aged 25 to 61 years were classified as amyloid (A)-/tau (T)-/neurodegeneration (N)-, 11.1% were A+/T-/(N)-, 5.6% were A+/T+/(N)-, and 9.3% were A+/T+/(N)+. The AT(N) profiles were associated with clinical Alzheimer's disease (AD) status and with memory performance, with the presence of T+ aligned with AD clinical symptomology. Findings inform models for predicting the transition to the prodromal stage of AD in DS.

Aerobic exercise, cardiorespiratory fitness, and the human hippocampus.

The hippocampus is particularly susceptible to neurodegeneration. Physical activity, specifically increasing cardiorespiratory fitness via aerobic exercise, shows promise as a potential method for mitigating hippocampal decline in humans. Numerous studies have now investigated associations between the structure and function of the hippocampus and engagement in physical activity. Still, there remains continued debate and confusion about the relationship between physical activity and the human hippocampus. In this review, we describe the current state of the physical activity and exercise literature as it pertains to the structure and function of the human hippocampus, focusing on four magnetic resonance imaging measures: volume, diffusion tensor imaging, resting-state functional connectivity, and perfusion. We conclude that, despite significant heterogeneity in study methods, populations of interest, and scope, there are consistent positive findings, suggesting a promising role for physical activity in promoting hippocampal structure and function throughout the lifespan.

Exercise interventions preserve hippocampal volume: A meta-analysis.

Hippocampal volume is a marker of brain health and is reduced with aging and neurological disease. Exercise may be effective at increasing and preserving hippocampal volume, potentially serving as a treatment for conditions associated with hippocampal atrophy (e.g., dementia). This meta-analysis aimed to identify whether exercise training has a positive effect on hippocampal volume and how population characteristics and exercise parameters moderate this effect. Studies met the following criteria: (a) controlled trials; (b) interventions of physical exercise; (c) included at least one time-point of hippocampal volume data before the intervention and one after; (d) assessed hippocampal volume using either manual or automated segmentation algorithms. Animal studies, voxel-based morphometry analyses, and multi-modal interventions (e.g., cognitive training or meditation) were excluded. The primary analysis in n = 23 interventions from 22 published studies revealed a significant positive effect of exercise on total hippocampal volume. The overall effect was significant in older samples (65 years of age or older) and in interventions that lasted over 24 weeks and had less than 150 min per week of exercise. These findings suggest that moderate amounts of exercise for interventions greater than 6 months have a positive effect on hippocampal volume including in older populations vulnerable to hippocampal atrophy.

Cardiovascular disease risk factors, tract-based structural connectomics, and cognition in older adults.

Cardiovascular disease risk factors (CVD-RFs) are associated with decreased gray and white matter integrity and cognitive impairment in older adults. Less is known regarding the interplay between CVD-RFs, brain structural connectome integrity, and cognition. We examined whether CVD-RFs were associated with measures of tract-based structural connectivity in 94 non-demented/non-depressed older adults and if alterations in connectivity mediated associations between CVD-RFs and cognition. Participants (age = 68.2 years; 52.1% female; 46.8% Black) underwent CVD-RF assessment, MRI, and cognitive evaluation. Framingham 10-year stroke risk (FSRP-10) quantified CVD-RFs. Graph theory analysis integrated T1-derived gray matter regions of interest (ROIs; 23 a-priori ROIs associated with CVD-RFs and dementia), and diffusion MRI-derived white matter tractography into connectivity matrices analyzed for local efficiency and nodal strength. A principal component analysis resulted in three rotated factor scores reflecting executive function (EF; FAS, Trail Making Test (TMT) B-A, Letter-Number Sequencing, Matrix Reasoning); attention/information processing (AIP; TMT-A, TMT-Motor, Digit Symbol); and memory (CVLT-II Trials 1-5 Total, Delayed Free Recall, Recognition Discriminability). Linear regressions between FSRP-10 and connectome ROIs adjusting for word reading, intracranial volume, and white matter hyperintensities revealed negative associations with nodal strength in eight ROIs (p-values<.05) and negative associations with efficiency in two ROIs, and a positive association in one ROI (p-values<.05). There was mediation of bilateral hippocampal strength on FSRP-10 and AIP, and left rostral middle frontal gyrus strength on FSRP-10 and AIP and EF. Stroke risk plays differential roles in connectivity and cognition, suggesting the importance of multi-modal neuroimaging biomarkers in understanding age-related CVD-RF burden and brain-behavior.

The Effects of High-Intensity Interval Training and Moderate Alcohol Consumption on Cognitive Performance-A Multidisciplinary Intervention in Young Healthy Adults.

BACKGROUND: The main purpose of this study was to determine the effects of a high-intensity interval training (HIIT) intervention in the context of moderate alcohol consumption on cognitive performance in healthy young adults. METHODS: We conducted a 10-week HIIT program along with four types of beverages with/without alcohol content. A total of 75 healthy adults (18-40 years old; 46% female) were allocated to either a control Non-Training group or an HIIT program group (2 days/week). Using block randomization, participants in the HIIT group were further allocated to an HIIT-Alcohol group (alcohol beer or sparkling water with vodka added, 5.4%) or an HIIT-NonAlcohol group (sparkling water or non-alcohol beer, 0.0%). The control group was instructed to maintain an active lifestyle but did not undergo any regular training. A comprehensive neuropsychological battery was used to evaluate cognitive performance (i.e., memory, working memory, processing speed, inhibitory control, and verbal fluency). Changes from baseline to week 10 were included in the main analyses. RESULTS: All groups improved in all neuropsychological measures (all p ≤ 0.001), independent of sex and alcohol consumption, with no statistical differences between groups (all p > 0.05). Furthermore, larger increases in maximal oxygen uptake were associated with greater improvements in processing speed, inhibitory control, and verbal fluency (all p < 0.050). CONCLUSIONS: Although the improvements found in cognitive performance cannot be attributed to the HIIT intervention, no significant impairments in cognitive functions were noted due to moderate alcohol intake. Furthermore, our results confirmed that exercise-induced physical fitness improvements were associated with cognitive performance enhancements in young healthy adults.

Cognitive and functional performance and plasma biomarkers of early Alzheimer's disease in Down syndrome.

INTRODUCTION: People with Down syndrome (DS) have a 75% to 90% lifetime risk of Alzheimer's disease (AD). AD pathology begins a decade or more prior to onset of clinical AD dementia in people with DS. It is not clear if plasma biomarkers of AD pathology are correlated with early cognitive and functional impairments in DS, and if these biomarkers could be used to track the early stages of AD in DS or to inform inclusion criteria for clinical AD treatment trials. METHODS: This large cross-sectional cohort study investigated the associations between plasma biomarkers of amyloid beta (Aß)42/40, total tau, and neurofilament light chain (NfL) and cognitive (episodic memory, visual-motor integration, and visuospatial abilities) and functional (adaptive behavior) impairments in 260 adults with DS without dementia (aged 25-81 years). RESULTS: In general linear models lower plasma Aß42/40 was related to lower visuospatial ability, higher total tau was related to lower episodic memory, and higher NfL was related to lower visuospatial ability and lower episodic memory. DISCUSSION: Plasma biomarkers may have utility in tracking AD pathology associated with early stages of cognitive decline in adults with DS, although associations were modest. Highlights: Plasma Alzheimer's disease (AD) biomarkers correlate with cognition prior to dementia in Down syndrome.Lower plasma amyloid beta 42/40 was related to lower visuospatial abilities.Higher plasma total tau and neurofilament light chain were associated with lower cognitive performance.Plasma biomarkers show potential for tracking early stages of AD symptomology.

Physical activity, memory function, and hippocampal volume in adults with Down syndrome.

Higher engagement in moderate-intensity physical activity (PA) is related to better cognitive functioning in neurotypical adults; however, little is known about the effect of PA on cognitive aging in adults with Down syndrome (DS). Individuals with DS have three copies of chromosome 21, which includes the gene involved in the production of the amyloid precursor protein, resulting in an increased risk for an earlier onset of Alzheimer's disease (AD). The goal of this study was to understand the relationship between engagement in moderate PA, memory, and hippocampal volume in adults with DS. Adults with DS participated in an ancillary Lifestyle study linked to the Alzheimer's Biomarkers Consortium for DS (ABC- DS; N = 71). A within-sample z-score memory composite was created from performance on the Cued Recall Test (CRT) and the Rivermead Picture Recognition Test. Participants wore a wrist-worn accelerometer (GT9X) to measure PA. Variables of interest included the average percentage of time spent in moderate PA and average daily steps. Structural MRI data were acquired within 18 months of actigraphy/cognitive data collection for a subset of participants (n = 54). Hippocampal volume was extracted using Freesurfer v5.3. Associations between moderate PA engagement, memory, and hippocampal volume were evaluated with hierarchical linear regressions controlling for relevant covariates [age, body mass index, intellectual disability level, sex, and intracranial volume]. Participants were 37.77 years old (SD = 8.21) and were 55.6% female. They spent 11.1% of their time engaged in moderate PA (SD = 7.5%) and took an average of 12,096.51 daily steps (SD = 4,315.66). After controlling for relevant covariates, higher memory composite score was associated with greater moderate PA engagement (ß = 0.232, p = 0.027) and more daily steps (ß = 0.209, p = 0.037). In a subset of participants, after controlling for relevant covariates, PA variables were not significantly associated with the hippocampal volume (all p-values ≥ 0.42). Greater hippocampal volume was associated with higher memory composite score after controlling for relevant covariates (ß = 0.316, p = 0.017). More PA engagement was related to better memory function in adults with DS. While greater hippocampal volume was related to better memory performance, it was not associated with PA. Greater PA engagement may be a promising lifestyle behavior to preserve memory in adults with DS.

The fitness versus body fat hypothesis in relation to hippocampal structure.

The Fitness Versus Body Fat Hypothesis argues that cardiorespiratory fitness (CRF) plays a more important role in cardiovascular health than adiposity. It remains poorly understood whether CRF or adiposity accounts for a greater amount of variation in measures of brain health. We examined the contribution of CRF, adiposity, and their interaction with hippocampal structure. This study included 124 sedentary adults (M = 44.34) with overweight/obesity (Body Mass Index mean = 32.43). FMRIB's Integrated Registration and Segmentation Tool was used to segment the hippocampus. Using hierarchical regression, we examined whether CRF, assessed via a submaximal graded exercise test, or adiposity, assessed as percent body fat using dual-energy x-ray absorptiometry (DXA) was associated with left and right hippocampal volume. Vertex-wise shape analysis was performed to examine regional shape differences associated with CRF and adiposity. Higher CRF was significantly associated with greater left hippocampal volume (p = .031), with outward shape differences along the surface of the subiculum and CA1 regions. Adiposity was not associated with left or right hippocampal volume or shape. The interaction between adiposity and CRF was not significant. Neither CRF nor adiposity were associated with thalamus or caudate nucleus volumes or shapes, two control regions. Higher CRF, but not adiposity, was related to greater left hippocampal volume, with outward shape differences along the surface of the subiculum and CA1 regions in a midlife sample with overweight/obesity. These findings indicate that, within the context of obesity, CRF is an important contributor to hippocampal structure, highlighting the importance of interventions targeting CRF.

A GENERALIZED FRAMEWORK OF PATHLENGTH ASSOCIATED COMMUNITY ESTIMATION FOR BRAIN STRUCTURAL NETWORK.

Diffusion MRI-derived brain structural network has been widely used in brain research and community or modular structure is one of popular network features, which can be extracted from network edge-derived pathlengths. Conceptually, brain structural network edges represent the connecting strength between pair of nodes, thus non-negative. The pathlength. Many studies have demonstrated that each brain network edge can be affected by many confounding factors (e.g. age, sex, etc.) and this influence varies on each edge. However, after applying generalized linear regression to remove those confounding's effects, some network edges may become negative, which leads to barriers in extracting the community structure. In this study, we propose a novel generalized framework to solve this negative edge issue in extracting the modular structure from brain structural network. We have compared our framework with traditional Q method. The results clearly demonstrated that our framework has significant advantages in both stability and sensitivity.

The Effects of a 12-Month Weight Loss Intervention on Cognitive Outcomes in Adults with Overweight and Obesity.

Obesity is associated with poorer executive functioning and reward sensitivity. Yet, we know very little about whether weight loss through diet and/or increased exercise engagement improves cognitive function. This study evaluated whether weight loss following a dietary and exercise intervention was associated with improved cognitive performance. We enrolled 125 middle-aged adults with overweight and obesity (98 female) into a 12-month behavioral weight loss intervention. Participants were assigned to one of three groups: energy-restricted diet alone, an energy-restricted diet plus 150 min of moderate intensity exercise per week or an energy restricted diet plus 250 min of exercise per week. All participants completed tests measuring executive functioning and/or reward sensitivity, including the Iowa Gambling Task (IGT). Following the intervention, weight significantly decreased in all groups. A MANCOVA controlling for age, sex and race revealed a significant multivariate effect of group on cognitive changes. Post-hoc ANCOVAs revealed a Group x Time interaction only on IGT reward sensitivity, such that the high exercise group improved their performance relative to the other two intervention groups. Post-hoc ANCOVAs also revealed a main effect of Time, independent of intervention group, on IGT net payoff score. Changes in weight were not associated with other changes in cognitive performance. Engaging in a high amount of exercise improved reward sensitivity above and beyond weight loss alone. This suggests that there is additional benefit to adding exercise into behavioral weight loss regimens on executive functioning, even without additional benefit to weight loss.

Higher Cardiorespiratory Fitness is Associated with Reduced Functional Brain Connectivity During Performance of the Stroop Task.

BACKGROUND: Although higher cardiorespiratory fitness (CRF) has been linked to better executive function, the mechanisms by which this occurs remain a matter of speculation. One hypothesis is that higher CRF is associated with elevated top-down control in which brain regions processing task-relevant information are up-regulated and brain regions processing task-irrelevant information are down-regulated. METHODS: We tested this top-down hypothesis in 50 young adults (µ age = 25.22 ±â€Š5.17 years) by measuring CRF via a graded maximal exercise test and performing functional Magnetic Resonance Imaging (fMRI) during a color-word Stroop task. We used task-evoked functional connectivity, quantified from a psychophysiological interaction analysis (PPI), to test our hypotheses that (a) higher CRF would be associated with greater connectivity between control centers (i.e., prefrontal and parietal areas) and visual feature centers (i.e., occipital areas) that are involved with processing task-relevant stimulus dimensions (i.e., color), and (b) higher CRF would be associated with lower connectivity between control centers and visual feature centers that are involved with processing task-irrelevant dimensions of the stimuli (i.e., word processing areas). RESULTS: Controlling for sex and BMI, we found, consistent with our second hypothesis, that higher CRF was associated with reduced functional connectivity between parietal and occipital areas involved in the task-irrelevant dimension of the task (i.e., word form areas). There were no associations between CRF and functional connectivity with the prefrontal cortex or evidence of heightened connectivity between attentional control and visual feature centers. CONCLUSIONS: These results suggest that CRF associations with executive functioning might be explained by CRF-mediated differences between brain regions involved with attentional control (parietal regions) and the down-regulation of regions involved with processing task-irrelevant stimulus features (occipital regions).

The oblique effect: The relationship between profiles of visuospatial preference, cognition, and brain connectomics in older adults.

The oblique effect (OE) describes the visuospatial advantage for identifying stimuli oriented horizontally or vertically rather than diagonally; little is known about brain aging and the OE. We investigated this relationship using the Judgment of Line Orientation (JLO) in 107 older adults (∼age = 67.8 ± 6.6; 51% female) together with neuropsychological tests of executive functioning (EF), attention/information processing (AIP), and neuroimaging. Only JLO lines falling between 36-54° or 126-144° were considered oblique. To quantify the oblique effect, we calculated z-scores for oblique errors (zOblique = #oblique errors/#oblique lines), and similarly, horizontal + vertical line errors (zHV), and a composite measure of oblique relative to HV errors (zOE). Composite z-scores of EF and AIP reflected domains associated with JLO performance. Graph theory analysis integrated T1-derived volumetry and diffusion MRI-derived white matter tractography into connectivity matrices analyzed for select network properties. Participants produced more zOblique than zHV errors (p < 0.001). Age was not associated with zOE adjusting for sex, education, and MMSE. Similarly adjusted linear regression models revealed that lower EF was associated with a larger oblique effect (p < 0.001). Modular analyses of neural connectivity revealed a differential patterns of network affiliation that varied by high versus low group status determined via median split of zOblique and zHV errors, separately. Older adults exhibit the oblique effect and it is associated with specific cognitive processes and regional brain networks that may facilitate future investigations of visuospatial preference in aging.