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Mild cognitive impairment (MCI) refers to cognitive alterations with preservation of functionality. Individuals with this diagnosis have a higher risk of developing dementia. Non-pharmacological interventions, such as physical exercise, are beneficial for the cognition of this population. However, the impact of resistance training (RT) on the brain anatomy of older adults with MCI has not yet been clarified. This study aimed to investigate the effects of RT on cognition and brain anatomy in MCI. Forty-four older adults with MCI, 22 in the training group and 22 in the control group, were evaluated in neuropsychological tests and magnetic resonance imaging at the beginning and end of the study, which lasted 24 weeks. We used repeated measures ANOVA. The training group showed better performance in verbal episodic memory after intervention. The control group showed a decrease in gray matter volume in the hippocampus and precuneus, while the training group showed no reduction in the right hippocampus and precuneus. However, it showed a decrease in the volume of these regions on the left side and in the left superior frontal gyrus. In the analysis of white matter integrity, fractional anisotropy increased in the training group and decreased in the control group. Axial diffusivity decreased in the training group, while radial diffusivity increased in the control group, and mean diffusivity varied according to the tract evaluated. RT improves memory performance, positively influences white matter integrity parameters, and plays a protective role against atrophy of the hippocampus and precuneus in MCI., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to American Aging Association.)

Healthy aging is associated with deficits in cognitive performance and brain changes, including in the cerebellum. Cerebellar communication with the cortex via closed-loop circuits through the thalamus have been established and these circuits are closely related to the functional topography of the cerebellum. In this study, we sought to elucidate relationships between cerebellar structure and function with cognition in healthy aging. We explored this relationship in 138 healthy adults (aged 35-86, 53% female) using resting-state functional connectivity MRI (fcMRI), cerebellar volume, and cognitive and motor assessments. Behavioral tasks assessed attention, processing speed, working memory, episodic memory, and motor abilities. We expected to find negative relationships between lobular volume with age, and positive relationships between specific lobular volumes with motor and cognitive behavior, respectively. We predicted lower cerebello-cortical fcMRI with increased age. Behaviorally, we expected higher cerebello-frontal and cerebello-association area fcMRI cerebellar connectivity to correlate with better behavioral performance. Correlations were conducted between cerebellar lobules I-IV, V, Crus I, Crus II, vermis VI and behavioral measures. We found lower volumes with increased age as well as both higher and lower cerebellar connectivity relationships with increased age, consistent with literature on functional connectivity and network segregation in aging. Further, we revealed unique associations between cerebellar structure and connectivity with comprehensive behavioral measures in a healthy aging population. Our findings further highlight the role of the cerebellum in aging., Competing Interests: Declarations. Conflict of interests: The authors have no relevant financial or non-financial interests to disclose. Ethical approval: This study was performed in line with the principles of the Institutional Review Board at Texas A&M University Human Subjects Protection Program. IRB number: IRB2015-0749D and approval date: 12/17/2019 with renewed approval 4/1/2024. Consent to participate: Informed consent was obtained from all individual participants included in the study. Consent to publish: All participant data is de-identified and additional personalized consent is not required for publication., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Several studies have aimed at identifying biomarkers in the initial phases of Alzheimer's disease (AD). Conversely, texture features, such as those from gray-level co-occurrence matrices (GLCMs), have highlighted important information from several types of medical images. More recently, texture-based brain networks have been shown to provide useful information in characterizing healthy individuals. However, no studies have yet explored the use of this type of network in the context of AD. This work aimed to employ texture brain networks to investigate the distinction between groups of patients with amnestic mild cognitive impairment (aMCI) and mild dementia due to AD, and a group of healthy subjects. Magnetic resonance (MR) images from the three groups acquired at two instances were used. Images were segmented and GLCM texture parameters were calculated for each region. Structural brain networks were generated using regions as nodes and the similarity among texture parameters as links, and graph theory was used to compute five network measures. An ANCOVA was performed for each network measure to assess statistical differences between groups. The thalamus showed significant differences between aMCI and AD patients for four network measures for the right hemisphere and one network measure for the left hemisphere. There were also significant differences between controls and AD patients for the left hippocampus, right superior parietal lobule, and right thalamus-one network measure each. These findings represent changes in the texture of these regions which can be associated with the cortical volume and thickness atrophies reported in the literature for AD. The texture networks showed potential to differentiate between aMCI and AD patients, as well as between controls and AD patients, offering a new tool to help understand these conditions and eventually aid early intervention and personalized treatment, thereby improving patient outcomes and advancing AD research., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Aging involves complex biological changes that affect disease susceptibility and aging trajectories. Although females typically live longer than males, they have a higher susceptibility to diseases like Alzheimer's, speculated to be influenced by menopause, and reduced ovarian hormone production. Understanding sex-specific differences is crucial for personalized medical interventions and gender equality in health. Our study aims to elucidate sex differences in regional cerebellar structure and connectivity during normal aging by investigating both structural and functional connectivity variations, with a focus on investigating these differences in the context of sex-steroid hormones. The study included 138 participants (mean age = 57(13.3) years, age range = 35-86 years, 54% women). The cohort was divided into three groups: 38 early middle-aged individuals (EMA) (mean age = 41(4.7) years), 48 late middle-aged individuals (LMA) (mean age = 58(4) years), and 42 older adults (OA) (mean age = 72(6.3) years). All participants underwent MRI scans, and saliva samples were collected for sex-steroid hormone quantification (17β-estradiol (E), progesterone (P), and testosterone (T)). We found less connectivity in females between Lobule I-IV and the cuneus, and greater connectivity in females between Crus I, Crus II, and the precuneus with increased age. Higher 17β-estradiol levels were linked to greater connectivity in Crus I and Crus II cerebellar subregions. Analyzing all participants together, testosterone was associated with both higher and lower connectivity in Lobule I-IV and Crus I, respectively, while higher progesterone levels were linked to lower connectivity in females. Structural differences were observed, with EMA males having larger volumes compared to LMA and OA groups, particularly in the right I-IV, right Crus I, right V, and right VI. EMA females showed higher volumes in the right lobules V and VI. These results highlight the significant role of sex hormones in modulating cerebellar connectivity and structure across adulthood, emphasizing the need to consider sex and hormonal status in neuroimaging studies to better understand age-related cognitive decline and neurological disorders.

Healthy aging is associated with deficits in cognitive performance and brain changes, including in the cerebellum. Yet, the precise link between cerebellar function/structure and cognition in aging remains poorly understood. We explored this relationship in 138 healthy adults (aged 35-86, 53% female) using resting-state functional connectivity MRI (fcMRI), cerebellar volume, and cognitive and motor assessments in an aging sample. We expected to find negative relationships between lobular volume for with age, and positive relationships between specific lobular volumes with motor and cognition respectively. We predicted lower cerebellar fcMRI to cortical networks and circuits with increased age. Behaviorally, we expected higher cerebello-frontal fcMRI cerebellar connectivity with association areas to correlate with better behavioral performance. Behavioral tasks broadly assessed attention, processing speed, working memory, episodic memory, and motor abilities. Correlations were conducted between cerebellar lobules I-IV, V, Crus I, Crus II, vermis VI and behavioral measures. We found lower volumes with increased age as well as bidirectional cerebellar connectivity relationships with increased age, consistent with literature on functional connectivity and network segregation in aging. Further, we revealed unique associations for both cerebellar structure and connectivity with comprehensive behavioral measures in a healthy aging population. Our findings underscore cerebellar involvement in behavior during aging.

The study here explores the link between transcranial direct current stimulation (tDCS) and brain-behavior relationships. We propose that tDCS may indirectly influence the complex relationships between brain volume and behavior. We focused on the dynamics between the hippocampus (HPC) and cerebellum (CB) in cognitive processes, a relationship with significant implications for understanding memory and motor skills. Seventy-four young adults (mean age: 22±0.42 years, mean education: 14.7±0.25 years) were randomly assigned to receive either anodal, cathodal, or sham stimulation. Following stimulation, participants completed computerized tasks assessing working memory and sequence learning in a magnetic resonance imaging (MRI) environment. We investigated the statistical interaction between CB and HPC volumes. Our findings showed that individuals with larger cerebellar volumes had shorter reaction times (RT) on a high-load working memory task in the sham stimulation group. In contrast, the anodal stimulation group exhibited faster RTs during the low-load working memory condition. These RT differences were associated with the cortical volumetric interaction between CB-HPC. Literature suggests that anodal stimulation down-regulates the CB and here, those with larger volumes perform more quickly, suggesting the potential need for additional cognitive resources to compensate for cerebellar downregulation. This new insight suggests that tDCS can aid in revealing structure-function relationships, due to greater performance variability, especially in young adults. It may also reveal new targets of interest in the study of aging or in diseases where there is also greater behavioral variability., Competing Interests: 7.Competing Interests The authors have no relevant financial or non-financial interests to disclose.

The causes of the neurodegenerative processes in Alzheimer's disease (AD) are not completely known. Recent studies have shown that white matter (WM) damage could be more severe and widespread than whole-brain cortical atrophy and that such damage may appear even before the damage to the gray matter (GM). In AD, Amyloid-beta (Aβ 42 ) and tau proteins could directly affect WM, spreading across brain networks. Since hippocampal atrophy is common in the early phase of disease, it is reasonable to expect that hippocampal volume (HV) might be also related to WM integrity. Our study aimed to evaluate the integrity of the whole-brain WM, through diffusion tensor imaging (DTI) parameters, in mild AD and amnestic mild cognitive impairment (aMCI) due to AD (with Aβ 42 alteration in cerebrospinal fluid [CSF]) in relation to controls; and possible correlations between those measures and the CSF levels of Aβ 42 , phosphorylated tau protein (p-Tau) and total tau (t-Tau). We found a widespread WM alteration in the groups, and we also observed correlations between p-Tau and t-Tau with tracts directly linked to mesial temporal lobe (MTL) structures (fornix and hippocampal cingulum). However, linear regressions showed that the HV better explained the variation found in the DTI measures (with weak to moderate effect sizes, explaining from 9% to 31%) than did CSF proteins. In conclusion, we found widespread alterations in WM integrity, particularly in regions commonly affected by the disease in our group of early-stage disease and patients with Alzheimer's disease. Nonetheless, in the statistical models, the HV better predicted the integrity of the MTL tracts than the biomarkers in CSF., (© 2022 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Males and females show differential patterns in connectivity in resting-state networks (RSNs) during normal aging, from early adulthood to late middle age. Age-related differences in network integration (effectiveness of specialized communication at the global network level) and segregation (functional specialization at the local level of specific brain regions) may also differ by sex. These differences may be due at least in part to endogenous hormonal fluctuation, such as that which occurs in females during midlife with the transition to menopause when levels of estrogens and progesterone drop markedly. A limited number of studies that have investigated sex differences in the action of steroid hormones in brain networks. Here we investigated how sex steroid hormones relate to age-network relationships in both males and females, with a focus on network segregation. Females displayed a significant quadratic relationship between age and network segregation for the cerebellar-basal ganglia and salience networks. In both cases, segregation was still increasing through adulthood, highest in midlife, and with a downturn thereafter. However, there were no significant relationships between sex steroid hormone levels and network segregation levels in females, and they did not exhibit significant associations between progesterone or 17β-estradiol and network segregation. Patterns of connectivity between the cerebellum and basal ganglia have been associated with cognitive performance and self-reported balance confidence in older adults. Together, these findings suggest that network segregation patterns with age in females vary by network, and that sex steroid hormones are not associated with this measure of connectivity in this cross-sectional analysis. Though this is a null effect, it remains critical for understanding the extent to which hormones relate to brain network architecture., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Hicks, Magalhães, Ballard, Jackson, Cox and Bernard.)

Purpose: Default mode network (DMN) has emerged as a potential biomarker of Alzheimer's disease (AD); however, it is not clear whether it can differentiate amnestic mild cognitive impairment with altered amyloid (aMCI-Aβ +) who will evolve to AD. We evaluated if structural and functional connectivity (FC), hippocampal volumes (HV), and cerebrospinal fluid biomarkers (CSF-Aβ 42 , p-Tau, and t-Tau) can differentiate aMCI-Aβ + converters from non-converters., Methods: Forty-eight individuals (18 normal controls and 30 aMCI subjects in the AD continuum - with altered Aβ 42 in the CSF) were followed up for an average of 13 months. We used MultiAtlas, UF 2 C, and Freesurfer software to evaluate diffusion tensor imaging, FC, and HV, respectively, INNOTEST® kits to measure CSF proteins, and neuropsychological tests. Besides, we performed different MANOVAs with further univariate analyses to differentiate groups., Results: During follow-up, 8/30 aMCI-Aβ + converted (26.6%) to AD dementia. There were no differences in multivariate analysis between groups in CSF biomarkers (p = 0.092) or at DMN functional connectivity (p = 0.814). aMCI-Aβ + converters had smaller right HV than controls (p = 0.013), and greater right cingulum parahippocampal bundle radial diffusivity than controls (p < 0.001) and non-converters (p = 0.036)., Conclusion: In this exploratory study, structural, but not functional, DMN connectivity alterations may differentiate aMCI-Aβ + subjects who converted to AD dementia., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Alzheimer's disease (AD) is a neurodegenerative condition that affects a large number of elderly people worldwide and has a high social and economic impact. The diagnosis of AD in early stage can significantly improve the evolution and prognosis of the disease. We report the use of A Disintegrin And Metalloprotease 10 (ADAM10) as a blood biomarker for the early diagnosis of AD. A simple, low-cost, sensitive, and disposable microfluidic platform (DμP) was developed for ADAM10 detection in plasma and cerebrospinal fluid based on electrochemical immunosensors. The assay was designed to accurately detect ADAM10 in serum, with a limit of detection of 0.35 fg/mL. ADAM10 was detected in subjects divided into cognitively healthy subjects, subjects with mild cognitive impairment, and AD patients in different disease stages. An increase in protein levels was found throughout the disease, and good DμP accuracy in differentiating individuals was observed. The DμP provided significantly better sensitivity than the well-established enzyme-linked immunosorbent assay test. ADAM10 and its detection using the DμP were proven to be an alternative tool for the early diagnosis and monitoring of AD, bringing new exciting possibilities to improve the quality of life of AD patients.

Introduction: Information about how physical exercise affects patients with amnestic mild cognitive impairment (aMCI) due to Alzheimer's disease (AD) is still missing. This study evaluated the impact of multicomponent exercise training on cognition and brain structure in aMCI subjects with cerebral spinal fluid positive AD biomarkers., Methods: Forty aMCI subjects were divided in training (multicomponent exercise thrice a week for 6 months) and nontraining groups. Assessments included cardiorespiratory fitness, neurocognitive tests, and a structural magnetic resonance imaging using 3.0 T scanner. FreeSurfer software analyzed hippocampal volume and cortical thickness., Results: The training group showed increased volume in both hippocampi and better performance in episodic memory test after 6 months. In contrast, the nontraining group declined in functional activities, recognition, and cardiorespiratory fitness for the same period., Discussion: Multicomponent exercise seems to improve hippocampal volume and episodic memory, and maintains VO 2max in aMCI due to AD.

Alzheimer's disease (AD) is the most common form of dementia, with no means of cure or prevention. The presence of abnormal disease-related proteins in the population is, in turn, much more common than the incidence of dementia. In this context, the cognitive reserve (CR) hypothesis has been proposed to explain the discontinuity between pathophysiological and clinical expression of AD, suggesting that CR mitigates the effects of pathology on clinical expression and cognition. fMRI studies of the human connectome have recently reported that AD patients present diminished functional efficiency in resting-state networks, leading to a loss in information flow and cognitive processing. No study has investigated, however, whether CR modifies the effects of the pathology in functional network efficiency in AD patients. We analyzed the relationship between CR, pathophysiology and network efficiency, and whether CR modifies the relationship between them. Fourteen mild AD, 28 amnestic mild cognitive impairment (aMCI) due to AD, and 28 controls were enrolled. We used education to measure CR, cerebrospinal fluid (CSF) biomarkers to evaluate pathophysiology, and graph metrics to measure network efficiency. We found no relationship between CR and CSF biomarkers; CR was related to higher network efficiency in all groups; and abnormal levels of CSF protein biomarkers were related to more efficient networks in the AD group. Education modified the effects of tau-related pathology in the aMCI and mild AD groups. Although higher CR might not protect individuals from developing AD pathophysiology, AD patients with higher CR are better able to cope with the effects of pathology-presenting more efficient networks despite pathology burden. The present study highlights that interventions focusing on cognitive stimulation might be useful to slow age-related cognitive decline or dementia and lengthen healthy aging.

There is increasing evidence suggesting that one of the most relevant pathophysiological features of Alzheimer's disease (AD) is neuroinflammation, which plays an important role in the production and regulation of AD-related proteins (amyloid beta (Aβ) and Tau) and exacerbates AD pathology. Neuroinflammation can also be induced by systemic influences (factors from outside the central nervous system). However, the role of systemic inflammation in AD pathophysiology is much less understood. Thus, our main objective in this study was to verify whether the presence of serum cytokines (IL-1β, IL-6, IL-10, IL-12, and TNF-α) affects different AD biomarkers: Aβ 1-42 and Tau protein levels, hippocampal volumes (HV), and default mode network functional connectivity (DMN FC) in healthy elderly controls, amnestic mild cognitive impairment (aMCI) patients due to AD, and mild AD patients. To accomplish this, we acquired 3-T MRI, blood, and cerebrospinal fluid (CSF) samples from 42 healthy controls, 55 aMCI patients due to AD, and 33 mild AD patients. Comparing the groups, we found that the mild AD patients presented smaller HV, disrupted DMN FC, and proportionally less IL-1β than the controls. The aMCI patients only differed from the controls in DMN FC. In intra-group comparison, aMCI and mild AD with detectable levels of cytokines (TNF-α, IL-1β, IL-10, and IL-12) had decreased DMN FC. On the other hand, patients with detectable levels of IL-10 and IL-12 presented a more favorable AD biomarkers profile (larger HV, more CSF Aβ 1-42 , and less p-Tau), indicating a possible protective role of these ILs. Our findings indicate a possible relationship between systemic inflammation with DMN FC disruption, hippocampal atrophy, and CSF protein levels in the subjects with mild AD and aMCI.

Background: In the last decade, many studies have reported abnormal connectivity within the default mode network (DMN) in patients with Alzheimer disease. Few studies, however, have investigated other networks and their association with pathophysiological proteins obtained from cerebrospinal fluid (CSF)., Methods: We performed 3 T imaging in patients with mild Alzheimer disease, patients with amnestic mild cognitive impairment (aMCI) and healthy controls, and we collected CSF samples from the patients with aMCI and mild Alzheimer disease. We analyzed 57 regions from 8 networks. Additionally, we performed correlation tests to investigate possible associations between the networks' functional connectivity and the protein levels obtained from the CSF of patients with aMCI and Alzheimer disease., Results: Our sample included 41 patients with Alzheimer disease, 35 with aMCI and 48 controls. We found that the main connectivity abnormalities in those with Alzheimer disease occurred between the DMN and task-positive networks: these patients presented not only a decreased anticorrelation between some regions, but also an inversion of the correlation signal (positive correlation instead of anticorrelation). Those with aMCI did not present statistically different connectivity from patients with Alzheimer disease or controls. Abnormal levels of CSF proteins were associated with functional disconnectivity between several regions in both the aMCI and mild Alzheimer disease groups, extending well beyond the DMN or temporal areas., Limitations: The presented data are cross-sectional in nature, and our findings are dependent on the choice of seed regions used., Conclusion: We found that the main functional connectivity abnormalities occur between the DMN and task-positive networks and that the pathological levels of CSF biomarkers correlate with functional connectivity disruption in patients with Alzheimer disease.