Women's Healthy Brain Project News
permalinkJustin Harris (University of Minnesota Legacy) - 2020-05-01
It was 2010, and Kunin and her friends and fellow philanthropists Barbara Forster and Sally Kling were meeting with Apostolos Georgopoulos, a Regents Professor and McKnight Presidential Chair in Cognitive Neuroscience at the University of Minnesota Medical School. Georgopoulos was asking for their support in launching a first-of-its-kind study of women's brain health across the lifespan.
He wanted to know: Why do some women show signs of cognitive decline as they age while others do not?
Kunin, Forster, and Kling were interested in helping him find answers. They shared the idea with other like-minded women, hosting small fundraising gatherings and meet-and-greets with Georgopoulos, and sent letters to more than 170 people asking for gifts of any size...
Dementia Prevention Linked to Disposal of Pathogenic Debris
permalinkUMN Inquiry - Deane Morrison - 2020-02-21
What if surviving an infection like herpes, pneumonia, or Lyme desease set you up for dementia later in life?
For some people that is, sadly, the case, studies by two University of Minnesota researchers indicate. Evidence is mounting that proteins in fragments of bacteria, viruses, or other pathogens left over from battles with our immune system can harm the brain and raise the chance of dementia. These proteins are all termed "antigenic" - i.e., able to provoke an immune response, especially one involving antibody production.
But Lisa James, PhD, and Apostolos Georgopoulos, MD, PhD, have also found that many people have genes that shield against such an outcome. And now they have demonstrated their beneficial effects across the populations of entire countries.
Article Continued at Publisher's Site.
Dementias Caused by Persistent Pathogens and the Protective Role of Human Leukocyte Antigen Against them
Human Leukocyte Antigen) in maintaining brain health by facilitating the elimination of pathogens and highlight evidence suggesting that the inability to eliminate pathogens contributes to dementia. Finally, we briefly review common forms of dementia including Alzheimer's disease, vascular dementia, frontotemporal dementia, Lewy body dementia, and prion dementia in an effort to contextualize the role of persistent pathogens across the various dementia phenotypes.
The Human Leukocyte Antigen DRB1*13:02 Allele Protects against Dementia in Continental Western Europe
Apolipoprotein E4 (
ApoE4), suggesting a possible protection against dementia. Here we evaluated the association between the population frequency of common DRB1*13 alleles and the prevalence of dementia in Continental Western Europe. Prevalence of dementia in Continental Western Europe was derived from published reports on dementia frequency from the Global Burden of Disease Study 2016 and population totals obtained from the Population Reference Bureau. DRB1*13:01 and DRB1*13:02 allele frequencies were obtained from a publicly available database (allelefrequency.net) and
ApoEwas obtained from published reports on the world distribution of
ApoE4. The prevalence of dementia in 14 Continental Western European (CWE) countries, where life expectancy is practically identical, significantly decreases exponentially with increasing frequency of DRB1*13:02 (R2 = 0.452, P = 0.008), even when adjusted for the prevalence of
ApoE4 allele, a known risk factor for Alzheimer's disease. This finding documents the protective effect of DRB1*13:02 on dementia prevalence in CWE. Since the function of
HLAclass II genes is to aid in the elimination of pathogens by enabling the production of antibodies against their antigens in specific immunity, the protective effect of DRB1*13:02 points to the presence of persistent harmful antigens as causal factors in development of dementia, antigens specific to DRB1*13:02 that could not be eliminated in its absence.
Human Leukocyte Antigen as a Key Factor in Preventing Dementia and Associated Apolipoprotein E4 Risk
permalinkFrontiers in Aging Neuroscience - 2019-04-12James L, Georgopoulos AP10.3389/fnagi.2019.00082Itzhaki's (2018) recent review discusses the evidence for a role of herpes virus (mainly herpes virus 1) in the development of Alzheimer's disease (AD), particularly among genetically vulnerable individuals. Specifically, the viral concept proposes that latent herpes virus in the brain of
ApoE4) carriers is intermittently reactivated causing cumulative damage that ultimately results in AD. The viral concept and collective findings are particularly intriguing given the potential for intervention for AD aimed at neutralizing or eliminating herpes virus. Here we discuss
HLAas an additional genetic link in the viral concept of AD that not only accounts for the role of herpes virus in AD, but also extends to other viruses that may contribute to AD and to other diseases, and is consistent with beneficial brain effects of treatments aimed at eliminating the damaging effects of herpes virus via antivirals or IVIG as discussed in the review.
The effects of Human Leukocyte Antigen DRB1*13 and Apolipoprotein E on age-related variability of Synchronous Neural Interactions in healthy women
permalinkEBioMedicine - 2018-09-01James L, Dolan S, Leuthold A, Engdahl B, Georgopoulos A, Georgopoulos AP10.1016/j.ebiom.2018.08.026Background
Age-related brain changes are well-documented and influenced by genetics. Extensive research links
ApoEto brain function, with the E4 allele serving as a risk factor for brain disease, including Alzheimer's disease, and the E2 allele conferring protection. Recent evidence also supports protective effects of another gene,
HLADRB1*13, on brain disease and age-related brain atrophy in cognitively healthy adults. Here we investigated the effects of
HLADRB1*13 on brain function by examining changes in neural network properties with age in healthy adults.
One hundred seventy-eight cognitively healthy women (28-99 y old) underwent a magnetoencephalography scan and provided a blood sample for genetic analysis. Age-related changes in neural network variability in genetic subgroups of DRB1*13 X
ApoEgenotype combinations were assessed using linear regression of network variability against age.
For individuals lacking a DRB1*13 allele and/or carrying an
ApoE4 allele, network variability increased significantly with age. In contrast, no such increase was observed in the presence of DRB1*13 and/or
These findings extend previous research documenting the protective effect of DRB1*13 on brain structure to include protection against age-related changes in brain function, and demonstrate similar protective effects on neural network variability for either DRB1*13 or
ApoE2. These protective effects could be due to reduction or elimination of factors known to disrupt brain function, including neuroinflammation and amyloid beta protein.
U.S. Department of Veterans Affairs, and University of Minnesota.
Minnesota Women's Healthy Brain Aging Project: Past, Present, and Future
permalink2018-06-12Lisa James, PhD, holder of the , presented her work at the University of Minnesota on June 12th, 2018. She, along with the project coordinator, Stacy Dolan, RN are shown describing and seeking support from an appreciative audience. Two attendees are shown with project assistant Rachel Johnson (right).
To learn more about our work and how you can support it, visit
Protective Effect of Human Leukocyte Antigen Allele DRB1*13:02 on Age-Related Brain Gray Matter Volume Reduction in Healthy Women
permalinkEBioMedicine - 2018-03-01James L, Savayan PC, Lewis S, Engdahl B, Georgopoulos A, Georgopoulos AP10.1016/j.ebiom.2018.02.005Background
Reduction of brain volume (brain atrophy) during healthy brain aging is well documented and dependent on genetic, lifestyle and environmental factors. Here we investigated the possible dependence of brain gray matter volume reduction in the absence of the
HLAallele DRB1*13:02 which prevents brain atrophy in
Gulf War Illness(James et al., 2017).
Seventy-one cognitively healthy women (32-69 years old) underwent a
Structural Magnetic Resonance Imagingscan to measure the volumes of total gray matter, cerebrocortical gray matter, and subcortical gray matter. Participants were assigned to two groups, depending on whether they lacked the DRB1*13:02 allele (No DRB1*13:02 group, N = 60) or carried the DRB1*13:02 allele (N = 11). We assessed the change of brain gray matter volume with age in each group by performing a linear regression where the brain volume (adjusted for total intracranial volume) was the dependent variable and age was the independent variable.
In the No DRB1*13:02 group, the volumes of total gray matter, cerebrocortical gray matter, and subcortical gray matter were reduced highly significantly. In contrast, none of these volumes showed a statistically significant reduction with age in the DRB1*13:02 group.
These findings document the protective effect of DRB1*13:02 on age-dependent reduction of brain gray matter in healthy individuals. Since the role of this allele is to connect to matching epitopes of external antigens for the subsequent production of antibodies and elimination of the offending antigen, we hypothesize that its protective effect may be due to the successful elimination of such antigens to which we are exposed during the lifespan, antigens that otherwise would persist causing gradual brain atrophy. In addition, we consider a possible beneficial role of DRB1*13:02 attributed to its binding to cathepsin S, a known harmful substance in brain aging (Wendt et al., 2008). Of course, other factors covarying with the presence of DRB1*13:02 could be involved.
The Exploration of Dietary Habits Associated with Healthy Brain Functioning Across the Lifespan
permalinkSociety for Neuroscience - 2016-01-01Mathison JH, James L, Hoover H, Georgopoulos A, Georgopoulos APThe Healthy Brain Project (HBP) is a unique study at the
Brain Sciences Centerthat integrates neuroimaging, genetics, cognitive, and lifestyle data in order to identify characteristics associated with healthy brain aging . Participants are cognitively healthy women veterans from ealty adulthood to advanced old age. Collecting such data from a healthy population could allow for more detailed identification of dietary habits associated with healthy brain function across the lifespan.
Neural Network Decorrelation for Healthy Brain Aging: A Cross-sectional and Longitudinal Magnetoencephalography study
permalinkSociety for Neuroscience - 2016-01-01James L, Leuthold A, Georgopoulos A, Chorn C, Mathison JH, Georgopoulos APNeural network decorrelation is fundamental to information processing. Specifically, ensemble freedom is constrained by correlations amount network elements: a network with least correlated elements provides maximum independence (i.e., zero mutual information) and hence entails maximum possibilities for encoding information.
We have previously demonstrated that neural decorrelation, primarily involving temporal regions, distinguishes healthy veterans from those with psychiatric disorders, and have hypothesized that network decorrelation underlies healthy brain functioning by permitting neural flexibility (James et al., JAMA Psychiatry 70:410-418). In the present study (http://healthybrain.umn.edu/), we tested the hypothesis that in cognitively healthy individuals, decorrelation would increase with age, serving as a mechanism that promotes efficient information processing and neural flexibility to maintain healthy brain functioning across the lifespan.
The number of cysteine residues per mole in Apolipoprotein E affects systematically SNI in women's healthy brains
permalinkExperimental Brain Research - 2013-05-01Leuthold A, Mahan M, Stanwyck JJ, Georgopoulos A, Georgopoulos AP10.1007/s00221-013-3464-xApoE is involved in lipid metabolism in the brain, but its effects on brain function are not understood. Three
ApoEisoforms (E4, E3, and E2) are the result of cysteine-arginine interchanges at two sites: there are zero interchanges in E4, one interchange in E3, and two interchanges in E2. The resulting six
ApoEgenotypes (E4/4, E4/3, E4/2, E3/3, E3/2, E2/2) yield five groups with respect to the number of cysteine residues per mole (CysR/mole), as follows.
ApoE4/4 has zero cysteine residues per mole (0-CysR/mole), E4/3 has one (1-CysR/mole), E4/2 and E3/3 each has two (2-CysR/mole), E3/2 has three (3-CysR/mole), and E2/2 has four (4-CysR/mole). The use of the number of CysR/mole to characterize the
ApoEmolecule converts the categorical
ApoEgenotype scale, consisting of 6 distinct genotypes above, to a 5-point continuous scale (0-4 CysR/mole). This allows the use of statistical analyses suitable for continuous variables (e.g. regression) to quantify the relations between various variables and
ApoE. Using such analyses, here, we show for the first time that
ApoEaffects in a graded and orderly manner neural communication, as assessed by analyzing the relation between the number of CysR/mole and
Magnetoencephalographyin 130 cognitively healthy women. At the one end of the CysR/mole range, the 4-CysR/mole (E2/2)
SNIdistribution had the highest mean, lowest variance, lowest range, and lowest coefficient of variation, whereas at the other end, 0-CysR/mole (E4/4)
SNIdistribution had the lowest mean, highest variance, highest range, and highest coefficient of variation. The special status of the 4-CysR/mole distribution was reinforced by the results of a hierarchical tree analysis where the 4-CysR/mole (E2/2)
SNIdistribution occupied a separate branch by itself and the remaining CysR/mole
SNIdistributions were placed at increasing distances from the 4-CysR/mole distribution, according to their number of CysR/mole, with the 0-CysR/mole (E4/4) being farthest away. These findings suggest that the 4-CysR/mole (E2/2)
SNIdistribution could serve as a reference distribution. When the
SNIdistributions of individual women were expressed as distances from this reference distribution, there was a substantial overlap among women of various CysR/mole. This refocuses the placement of individual brains along a continuous distance from the 4-CysR/mole
SNIdistribution, in contrast to the common categorical assignment to a specific
ApoEgenotype. Finally, the orderly variation of
SNIwith the number of CysR/mole found here is in keeping with recent advances and ideas regarding the molecular mechanisms underlying the differential effects of
ApoEin the brain which emphasize the healthier stability conferred on the
ApoEmolecule by the increasing number of cysteine-arginine interchanges, with 4-CysR/mole (E2/2) being the best case, as opposed to the instability and increased chance of toxic fragmentation of the
ApoEmolecule with lower number of CysR/mole, with 0-CysR/mole (E4/4) as the worst case (Mahley and Huang in Neuron 76:871-885, 2012a). However, our results also document the appreciable variation of
SNIproperties within the various CysR/mole groups and individuals which points to the existence and important role of other factors involved in shaping brain function at the network level.