Introduction: Fasting glucose increases with age and is linked to modifiable Alzheimer's disease risk factors such as cardiovascular disease and Type 2 diabetes (T2D). Methods: We leveraged available biospecimens and neuroimaging measures... more
Introduction: Fasting glucose increases with age and is linked to modifiable Alzheimer's disease risk factors such as cardiovascular disease and Type 2 diabetes (T2D). Methods: We leveraged available biospecimens and neuroimaging measures collected during the Alzheimer's Prevention Through Exercise (APEx) trial (n = 105) to examine the longitudinal relationship between change in blood glucose metabolism and change in regional cerebral amyloid deposition and gray and white matter (WM) neurodegeneration in older adults over 1 year of follow-up. Results: Individuals with improving fasting glucose (n = 61) exhibited less atrophy and regional amyloid accumulation compared to those whose fasting glucose worsened over 1 year (n = 44). Specifically, while individuals with increasing fasting glucose did not yet show cognitive decline, they did have regional atrophy in the hippocampus and inferior parietal cortex, and increased amyloid accumulation in the precuneus cortex. Signs of early dementia pathology occurred in the absence of significant group differences in insulin or body composition, and was not modified by apolipoprotein E ε4 carrier status. Discussion: Dysregulation of glucose in late life may signal preclinical brain change prior to clinically relevant cognitive decline. Additional work is needed to determine whether treatments specifically targeting fasting glucose levels may impact change in brain structure or cerebral amyloid in older adults.
Background: First-degree relatives of individuals with late-onset Alzheimer's disease (AD) have increased risk for AD, with children of affected parents at an especially high risk. Objective: We aimed to investigate default mode network... more
Background: First-degree relatives of individuals with late-onset Alzheimer's disease (AD) have increased risk for AD, with children of affected parents at an especially high risk. Objective: We aimed to investigate default mode network connectivity, medial temporal cortex volume, and cognition in cognitively healthy (CH) individuals with (FH+) and without (FH-) a family history of AD, alongside amnestic mild cognitive impairment (aMCI) and AD individuals, to determine the context and directionality of dysfunction in at-risk individuals. Our primary hypothesis was that there would be a linear decline (CH FH-> CH FH+ > aMCI > AD) within the risk groups on all measures of AD risk. Methods: We used MRI and fMRI to study cognitively healthy individuals (n = 28) with and without AD family history (FH+ and FH-, respectively), those with aMCI (n = 31) and early-stage AD (n = 25). We tested connectivity within the default mode network, as well as measures of volume and thickness within the medial temporal cortex and selected seed regions. Results: As expected, we identified decreased medial temporal cortex volumes in the aMCI and AD groups compared to cognitively healthy groups. We also observed patterns of connectivity across risk groups that suggest a nonlinear relationship of change, such that the FH+ group showed increased connectivity compared to the FH-and AD groups (CH FH+ > CH FH-> aMCI > AD). This pattern emerged primarily in connectivity between the precuneus and frontal regions. Conclusion: These results add to a growing literature that suggests compensatory brain function in otherwise cognitively healthy individuals with a family history of AD.
Research Interests:
Research Interests: Genetics, Violence, Cognitive Control, Polymorphism, Risk, and 17 moreFunctional MRI, Emotion Regulation, Gene expression, Multidisciplinary, Emotions, Serotonin, Humans, Male, Functional Assessment, Focus, Neurons, Human Brain, Genotype, Limbic System, Brain Structure, Monoamine oxidase, and X chromosome inactivation
We compared white matter integrity with brain atrophy in healthy controls and participants with very mild dementia (Clinical Dementia Rating 0 vs. 0.5) from the Brain Aging Project, a longitudinal study of aging and memory at the... more
We compared white matter integrity with brain atrophy in healthy controls and participants with very mild dementia (Clinical Dementia Rating 0 vs. 0.5) from the Brain Aging Project, a longitudinal study of aging and memory at the University of Kansas Medical Center. Structural magnetic resonance imaging and diffusion tensor imaging (DTI) including fractional anisotropy and mean diffusivity were performed on 27 patients with very mild dementia (Clinical Dementia Rating = 0.5) of the Alzheimer's type (DAT), and 32 cognitively normal subjects. Patient groups were compared across 6 volumetric measures and 14 DTI regions of interest. Very mildly demented patients showed expected disease-related patterns of brain atrophy with reductions in whole-brain and hippocampal volumes most prominent. DTI indices of white matter integrity were mixed. Right parahippocampus showed significant but small disease-related reductions in fractional anisotropy. Right parahippocampus and left internal cap...
Research Interests:
Regulator of G-protein signaling 4 (RGS4) modulates postsynaptic signal transduction by affecting the kinetics of G alpha-GTP binding. Linkage, association, and postmortem studies have implicated the gene encoding RGS4 (RGS4) as a... more
Regulator of G-protein signaling 4 (RGS4) modulates postsynaptic signal transduction by affecting the kinetics of G alpha-GTP binding. Linkage, association, and postmortem studies have implicated the gene encoding RGS4 (RGS4) as a schizophrenia susceptibility factor. Using a multimodal neuroimaging approach, we demonstrate that genetic variation in RGS4 is associated with functional activation and connectivity during working memory in the absence of overt behavioral differences, with regional gray and white matter volume and with gray matter structural connectivity in healthy human subjects. Specifically, variation at one RGS4 single nucleotide polymorphism that has been associated previously with psychosis (rs951436) impacts frontoparietal and frontotemporal blood oxygenation level-dependent response and network coupling during working memory and results in regionally specific reductions in gray and white matter structural volume in individuals carrying the A allele. These findings suggest mechanisms in brain for the association of RGS4 with risk for psychiatric illness.
Research Interests:
Research Interests: Cognitive Science, Psychiatry, Statistical Analysis, Anisotropy, Global change, and 19 moreBrain, Humans, Standard Deviation, Female, Male, Statistical Significance, Cohort Study, Follow-up studies, Measurement Error, Coefficient of Variation, Clinical Sciences, Repeated Measures, Adult, Analysis of Variance, Fractional Anisotropy, Neurosciences, Region of Interest, Cohort Studies, and Mean Diffusivity
Research Interests: Animal Behavior, Schizophrenia, Social Interaction, Molecular Evolution, Magnetic Resonance Imaging, and 15 moreMultidisciplinary, Information Processing, Brain, Humans, Mice, G protein-coupled receptors, Animals, Male, Risk factors, Dentate Gyrus, Weight Reduction, Brain Structure, Risk Factors, Amino Acid Sequence, and Gray Matter
The question as to whether fitness should be assessed in a European health monitoring system, perhaps from the early stages of life onwards, remains to be answered. We aimed to examine the associations between cardiorespiratory fitness... more
The question as to whether fitness should be assessed in a European health monitoring system, perhaps from the early stages of life onwards, remains to be answered. We aimed to examine the associations between cardiorespiratory fitness and metabolic risk factors in children. A total of 873 healthy children from Sweden and Estonia aged 9–10 years (444 girls and 429 boys)
Research Interests:
Research Interests:
Research Interests: Schizophrenia, Magnetic Resonance Imaging, Biological Sciences, Biological Psychiatry, Software, and 19 moreHippocampus, Brain, Humans, Genetic Testing, Cerebral Cortex, Female, Voxel Based Morphometry, Male, Biological, Three Dimensional Imaging, Siblings, Risk factors, Phenotype, Schizotypal Personality Disorder, Middle Aged, Adult, Psychotic Disorders, Risk Factors, and Gray Matter
Research Interests: Neuroimaging, Magnetic Resonance Imaging, Aging, Biological Sciences, Insulin Resistance, and 23 moreHippocampus, Humans, Insulin, Female, Male, Physical sciences, Follow-up studies, Insulin signaling, Cognitive Performance, Clinical Sciences, Brain atrophy, Aged, Atrophy, Neurodegenerative Disease, Disease Progression, Cognitive Decline, Glucose Tolerance Test, Alzheimer Disease, Area Under the Curve, Area Under Curve, Cognition disorders, Biochemistry and cell biology, and Cohort Studies
To examine exercise testing response in Alzheimer's disease (AD) and possible disease-related change over time. Retrospective assessment of a 2-year observational study.... more
To examine exercise testing response in Alzheimer's disease (AD) and possible disease-related change over time. Retrospective assessment of a 2-year observational study. University medical center. Individuals without dementia (n=50) and with AD (n=31). Not applicable. Participants underwent a clinical dementia evaluation and performed an incremental exercise test using a treadmill and the modified Bruce protocol at baseline and at a 2-year follow-up. We examined oxygen consumption, minute ventilation, heart rate, and ventilatory equivalents for oxygen and carbon dioxide at submaximal and peak exercise intensities to determine whether the measures were different between groups or over time. Participants with AD and those without dementia performed similarly at submaximal effort, and both groups showed similar changes in exercise response over 2 years. However, nondemented individuals had consistently higher values of oxygen consumption (P≤.02) and minute ventilation at peak effort at baseline (P=.003). Individuals with AD demonstrate physiologic responses to submaximal exercise effort that are not significantly different than individuals without dementia. However, differences are apparent at the extreme of effort.
Research Interests:
Research Interests:
Research Interests:
Research Interests:
Research Interests:
Research Interests:
We have employed structural equation models to explicitly distinguish dementia-relevant variance in cognitive task performance (i.e., δ) from the variance that is unrelated to a dementing process (i.e.,... more
We have employed structural equation models to explicitly distinguish dementia-relevant variance in cognitive task performance (i.e., δ) from the variance that is unrelated to a dementing process (i.e., g'). Together g' and d comprise Spearman's "g". Although d represents only a minor fraction of the total variance in cognitive task performance, it is more strongly associated with dementia severity than is g'. In this analysis, we replicate δ in a new dataspace, the University of Kansas Brain Aging Project, and associate it specifically with regional grey matter atrophy by voxel-based morphometry of magnetic resonance imaging data. The latent variable d localizes to elements of the default mode network and related structures in the R hemisphere.
Research Interests:
Research Interests:
Research Interests:
ABSTRACTBackgroundEvidence increasingly suggests cerebrovascular dysfunction plays an early and important role in the pathogenesis of Alzheimer’s disease (AD). Studies have shown the strongest known genetic risk factor for sporadic AD,... more
ABSTRACTBackgroundEvidence increasingly suggests cerebrovascular dysfunction plays an early and important role in the pathogenesis of Alzheimer’s disease (AD). Studies have shown the strongest known genetic risk factor for sporadic AD, Apolipoprotein E4 (APOE4), may act synergistically with vascular risk factors to promote dementia development. Aerobic exercise may attenuate cognitive decline at least partially through improvements in cerebral blood flow. Therefore, exercise interventions that improve vascular health may be particularly beneficial for APOE4 carriers.ObjectivesTo test the hypothesis that exercise would more effectively increase hippocampal blood flow (HBF) in hypertensive APOE4 carriers than non-carriers, we performed an analysis of arterial spin labeling MRI data (ASL-MRI) from a randomized controlled trial (secondary outcome). Additionally, we tested the hypothesis that changes in systolic blood pressure (ΔSBP) would be more negatively associated with ΔHBF for APOE...
Research Interests:
Research Interests:
Research Interests: Cognitive Science, Dementia, Magnetic Resonance Imaging, Family history, Brain Mapping, and 15 moreBrain, Humans, Female, Male, Apolipoprotein E, Clinical Sciences, Aged, Atrophy, Genotype, Cross Sectional Studies, Alzheimer Disease, Early Diagnosis, Gray Matter, Inheritance Patterns, and Cohort Studies
BackgroundPhysical exercise may support brain health and cognition over the course of typical aging. The goal of this nonrandomized clinical trial was to examine the effect of an acute bout of aerobic exercise on brain blood flow and... more
BackgroundPhysical exercise may support brain health and cognition over the course of typical aging. The goal of this nonrandomized clinical trial was to examine the effect of an acute bout of aerobic exercise on brain blood flow and blood neurotrophic factors associated with exercise response and brain function in older adults with and without possession of the APOE4 allele, a genetic risk factor for developing Alzheimer’s. We hypothesized that older adult APOE4 carriers would have lower cerebral blood flow regulation and would demonstrate blunted neurotrophic response to exercise compared to noncarriers.MethodsSixty-two older adults (73±5 years old, 41 female) consented to this prospectively enrolling clinical trial, utilizing a single arm, single visit, experimental design, with post-hoc assessment of difference in outcomes based on APOE4 carriership. All participants completed a single 15-minute bout of moderate-intensity aerobic exercise. The primary outcome measure was change ...
Research Interests:
Research Interests: Cognitive Science, Neurology, Magnetic Resonance Imaging, Mild Cognitive Impairment, Positron Emission Tomography, and 15 moreOverweight, Humans, Female, Male, Follow-up studies, Body Mass Index, Clinical Sciences, Aged, Biological markers, Thiazoles, Cross Sectional Studies, Alzheimer Disease, Neurosciences, aniline Compounds, and Tau proteins
There is increasing interest in the role of physical exercise as a therapeutic strategy for individuals with Alzheimer's disease (AD). We assessed the effect of 26 weeks (6 months) of a supervised aerobic exercise program on memory,... more
There is increasing interest in the role of physical exercise as a therapeutic strategy for individuals with Alzheimer's disease (AD). We assessed the effect of 26 weeks (6 months) of a supervised aerobic exercise program on memory, executive function, functional ability and depression in early AD. This study was a 26-week randomized controlled trial comparing the effects of 150 minutes per week of aerobic exercise vs. non-aerobic stretching and toning control intervention in individuals with early AD. A total of 76 well-characterized older adults with probable AD (mean age 72.9 [7.7]) were enrolled and 68 participants completed the study. Exercise was conducted with supervision and monitoring by trained exercise specialists. Neuropsychological tests and surveys were conducted at baseline,13, and 26 weeks to assess memory and executive function composite scores, functional ability (Disability Assessment for Dementia), and depressive symptoms (Cornell Scale for Depression in Deme...
Research Interests:
To compare regional brain volume predictors of percent weight loss (WL) in dieters with obesity (DwO) and in the same participants categorized as "successful" (≥7% WL) or "unsuccessful" dieters (<7% WL). DwO (n =... more
To compare regional brain volume predictors of percent weight loss (WL) in dieters with obesity (DwO) and in the same participants categorized as "successful" (≥7% WL) or "unsuccessful" dieters (<7% WL). DwO (n = 72) and participants with healthy weight (n = 22) completed a structural MRI at baseline and 3 months. All DwO participants were enrolled in a 12-week program consisting of a reduced calorie diet, increased physical activity, and behavioral modification. SPM8-based voxel-based morphometry processing streams were used for measurements of regional gray (GMV) and white matter volume and longitudinal changes in volume. Correlations between WL and baseline brain volume and change in brain volume, as well as differences between groups, were then tested. %WL was positively correlated with baseline GMV in right parahippocampal and orbitofrontal gyri in DwO. Successful dieters showed greater GMV loss in the left precentral gyrus and the insula compared with un...
Research Interests:
End-stage renal disease (ESRD) is a disease with an aging population and a high prevalence of cognitive impairment affecting quality of life, health care costs and mortality. Structural changes in the brain with decreased white matter... more
End-stage renal disease (ESRD) is a disease with an aging population and a high prevalence of cognitive impairment affecting quality of life, health care costs and mortality. Structural changes in the brain with decreased white matter integrity have been observed in ESRD. Understanding the changes in cognition and associated changes in brain structure after renal transplantation can help define the mechanisms underlying cognitive impairment in ESRD. We conducted a prospective, observational cohort study in ESRD patients listed for renal transplantation and followed them post-transplantation. We assessed their cognitive function with a battery of neuropsychological tests and brain white matter integrity with diffusion tensor imaging (DTI) both before transplant and 3 months after transplant. Eleven patients, aged 56.5 ± 10.7 years, completed the study. Cognitive measures of memory and executive function improved after the transplant, specifically on tests of logical memory I (p = 0.0...
Research Interests: Cognition, Aging, Quality of life, Diffusion Tensor Imaging, Kidney transplantation, and 15 moreExecutive Function, Memory, Prospective studies, Humans, Female, Male, Follow-up studies, Clinical Sciences, Aged, Prevalence, Middle Aged, White matter, Cohort Studies, Neuropsychological Tests, and Cognitive dysfunction
Although Alzheimer's disease (AD) is the most common neurodegenerative disease, the etiology of AD is not well understood. In some cases, genetic factors explain AD risk, but a high percentage of late-onset AD is unexplained. The fact... more
Although Alzheimer's disease (AD) is the most common neurodegenerative disease, the etiology of AD is not well understood. In some cases, genetic factors explain AD risk, but a high percentage of late-onset AD is unexplained. The fact that AD is associated with a number of physical and systemic manifestations suggests that AD is a multifactorial disease that affects both the CNS and periphery. Interestingly, a common feature of many systemic processes linked to AD is involvement in energy metabolism. The goals of this review are to 1) explore the evidence that peripheral processes contribute to AD risk, 2) explore ways that AD modulates whole-body changes, and 3) discuss the role of genetics, mitochondria, and vascular mechanisms as underlying factors that could mediate both central and peripheral manifestations of AD. Despite efforts to strictly define AD as a homogeneous CNS disease, there may be no single etiologic pathway leading to the syndrome of AD dementia. Rather, the n...
Research Interests:
Depressive symptoms are associated with an increased risk of Alzheimer's disease (AD) but the mechanism(s) involved has not been well established. In a convenience sample of participants in the University of Kansas' Brain Aging... more
Depressive symptoms are associated with an increased risk of Alzheimer's disease (AD) but the mechanism(s) involved has not been well established. In a convenience sample of participants in the University of Kansas' Brain Aging Project, we use structural equation modeling (SEM) to explicitly distinguish depressive symptom-related variance in cognitive task performance (i.e., DEPCOG) from that which is unrelated to a depressive symptoms. DEPCOG is strongly associated with the cognitive correlates of functional status (δ), which we previously associated with elements of the Default Mode Network (DMN). Both δ and DEPCOG map to a posterior cingulate seeded network that has recently been associated with amyloid-β deposition and includes elements of the DMN. Both contribute significantly to clinical dementia status and dementia severity, as measured by the Clinical Dementia Rating Scale Sum of Boxes. These findings suggest that the cognitive correlates of depressive symptoms, even...
Research Interests:
A family history of Alzheimer's disease (AD) increases one's risk of developing late-onset AD (LOAD), and a maternal family history of LOAD influences risk more than a paternal family history. Accumulating evidence suggests that a... more
A family history of Alzheimer's disease (AD) increases one's risk of developing late-onset AD (LOAD), and a maternal family history of LOAD influences risk more than a paternal family history. Accumulating evidence suggests that a family history of dementia associates with AD-typical biomarker changes. We analyzed cross-sectional data from non-demented, mild cognitive impairment (MCI), and LOAD participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) with PET imaging using Pittsburgh Compound B (PiB, n = 99) and cerebrospinal fluid (CSF) analysis (n = 403) for amyloid-β peptide (Aβ) and total tau. We assessed the relationship of CSF and PiB biomarkers and family history of dementia, as well as parent gender effects. In the larger analysis of CSF biomarkers, we assessed diagnosis groups individually. In the overall sample, CSF Aβ, tau/Aβ ratio, and global PiB uptake were significantly different between family history positive and negative groups, with marker...
Research Interests:
Research Interests:
Research Interests:
Research Interests: Neuroscience, Metabolism, Magnetic Resonance Imaging, Linear models, Insulin Resistance, and 15 moreBrain, Humans, Fasting, Female, Male, Aged, Glucose Tolerance Test, Cross Sectional Studies, Alzheimer Disease, Neurosciences, Gray Matter, Parkinson Disease, Ad, Motor activity, and Neuropsychological Tests
Research Interests:
Research Interests:
Research Interests:
Research Interests:
Research Interests:
Neuroimaging studies of apolipoprotein E (ApoE4) have implicated its association with brain atrophy in Alzheimer's disease. To date, few studies have used automated morphological analysis techniques to assess ApoE4-related brain... more
Neuroimaging studies of apolipoprotein E (ApoE4) have implicated its association with brain atrophy in Alzheimer's disease. To date, few studies have used automated morphological analysis techniques to assess ApoE4-related brain structure change in both gray and white matter in nondemented older adults. Nondemented (CDR = 0, n = 53) subjects over 60 had MRI, diffusion tensor imaging, and neurocognitive assessments. We assessed differences in cognition and brain structure associated with ApoE4 genetic variation using voxel-based morphometry techniques, and tract-based spatial statistics of fractional anisotropy change. In nondemented older adults with the E4 allele, cognitive performance was reduced, and atrophy was present in the hippocampus and amygdala compared to ApoE4 negative participants. We also report that E4 carriers have decreased fractional anisotropy in the left parahippocampal gyrus white matter. In conclusion, the presence of an ApoE4 allele in nondemented older ad...
Research Interests: Cognitive Science, Magnetic Resonance Imaging, Aging, Diffusion Tensor Imaging, Anisotropy, and 15 moreActivities of Daily Living, Brain, Humans, Female, Male, Amygdala, Apolipoprotein E, Health Status, Clinical Sciences, Aged, Middle Aged, Genotype, Alzheimer Disease, Neurosciences, and Motor activity
Research Interests: Cognitive Science, Magnetic Resonance Imaging, Brain Mapping, Brain, Humans, and 14 moreFemale, Male, Bone Density, Clinical Sciences, Aged, Atrophy, Age Factors, Alzheimer Disease, Neurosciences, Bone Resorption, Cognition disorders, Case Control Studies, Severity of Illness Index, and Neuropsychological Tests
There is increasing evidence for subtle motor dysfunction early in Alzheimer disease (AD), including common motor behaviors that were once considered unaffected early in the disease process. Our objective was to assess whether functional... more
There is increasing evidence for subtle motor dysfunction early in Alzheimer disease (AD), including common motor behaviors that were once considered unaffected early in the disease process. Our objective was to assess whether functional neural networks underlying motor behavior are altered by AD. We investigated AD-related differences in regional brain activation during motor performance. Nine older adults with early-stage AD and 10 without dementia underwent functional magnetic resonance imaging while performing a visually directed simple motor task (hand squeeze). Despite some similarity in brain activation during motor performance, we found that individuals without dementia exhibited greater activation in accessory motor regions, supplementary motor area, and cerebellum compared with those with AD. We also assessed disease-related differences in regions where activity was functionally integrated with primary motor cortex. Using a psychophysiological interaction analysis, we foun...
Research Interests: Magnetic Resonance Imaging, Risk assessment, Brain Mapping, Humans, Female, and 15 moreMale, Motor Cortex, Aged, Middle Aged, Analysis of Variance, Prognosis, Age Factors, Risk Assessment, Neural pathways, Reference Values, Alzheimer Disease, Motor Skills, Case Control Studies, Psychomotor Performance, and Severity of Illness Index
Despite mounting evidence that physical activity has positive benefits for brain and cognitive health, there has been little characterization of the relationship between cardiorespiratory (CR) fitness and cognition-associated brain... more
Despite mounting evidence that physical activity has positive benefits for brain and cognitive health, there has been little characterization of the relationship between cardiorespiratory (CR) fitness and cognition-associated brain activity as measured by functional magnetic resonance imaging (fMRI). The lack of evidence is particularly glaring for diseases such as Alzheimer disease (AD) that degrade cognitive and functional performance. The aim of this study was to describe the relationship between regional brain activity during cognitive tasks and CR fitness level in people with and without AD. A case-control, single-observation study design was used. Thirty-four individuals (18 without dementia and 16 in the earliest stages of AD) completed maximal exercise testing and performed a Stroop task during fMRI. Cardiorespiratory fitness was inversely associated with anterior cingulate activity in the participants without dementia (r=-.48, P=.05) and unassociated with activation in those with AD (P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;.7). Weak associations of CR fitness and middle frontal cortex were noted. The wide age range and the use of a single task in fMRI rather than multiple tasks challenging different cognitive capacities were limitations of the study. The results offer further support of the relationship between CR fitness and regional brain activity. However, this relationship may be attenuated by disease. Future work in this area may provide clinicians and researchers with interpretable and dependable regional fMRI biomarker signatures responsive to exercise intervention. It also may shed light on mechanisms by which exercise can support cognitive function.