Brain Function News
Association of Lupus Anticoagulant with Brain Atrophy in Gulf War Illness
permalinkJournal of Immunological Sciences - 2021-05-27James L, Christova P, Johnson R, Engdahl B, Lewis S, Carpenter A, Georgopoulos APSeparate lines of research have documented brain atrophy and evidence of autoimmune mechanisms in
Gulf War Illness, including the presence of lupus anticoagulant (LAC), in veterans with
GWI. Here we evaluated the possible association of LAC and brain volume in veterans with
GWI. The presence of LAC was determined using Silica Clotting Time and dilute Russell's Viper Venom Time assays. MRI data was acquired using a Philips 3T MR scanner from which total gray matter, total cortical gray matter, total subcortical gray matter, and total cerebral white matter were derived. The results demonstrated a statistically significant reduction of brain volume in all regions tested in
GWIveterans with positive LAC, as compared to those without LAC. These findings add to the literature implicating autoimmune mechanisms in
GWIand point to the presence of prothrombotic antiphospholipid antibodies as contributing to brain atrophy in
Immunogenetic Epidemiology of Multiple Sclerosis in 14 Continental Western European Countries
Human Leukocyte AntigenDRB1*15:01 exerts the strongest susceptibility effect, although other
HLAalleles have been implicated in both susceptibility to, and protection against, MS. Here we utilized an immunogenetic epidemiological approach to evaluate correlations between the population frequencies of 127
HLAClass I and II alleles and the population prevalence of MS in 14 Continental Western European countries to identify an
HLAprofile for MS. The results of these analyses, which largely corroborated prior findings and revealed several novel and highly robust
HLAassociations with MS, revealed a larger number of protective
HLAalleles than susceptibility alleles, particularly for
HLAClass I. Given the role of
HLAin pathogen elimination and autoimmunity, these findings point to a contributory role of exposure to pathogens in the absence of protective
HLAin underlying the inflammation and autoimmunity associated with MS.
Lupus Anticoagulant in Gulf War Illness and Autoimmune Disorders: A Common Pathway Toward Autoimmunity
permalinkJournal of Immunological Sciences - 2021-02-25James L, Johnson R, Lewis S, Carpenter A, Engdahl B, Krug HE, Georgopoulos APMounting evidence suggests that autoimmune mechanisms may underlie the chronic symptoms characteristic of
GWI. The presence of antiphospholipid antibodies including Lupus Anticoagulant (LA) are often associated with autoimmune disorders. Here we evaluated and compared blood samples from veterans with
GWIand veterans with other autoimmune conditions including relapsing remitting multiple sclerosis, rheumatoid arthritis, Sj"ogren's syndrome, and lupus for the presence of LA using Silica Clotting Time and dilute Russell's Viper Venom Time assays. Positive LA was identified in one-quarter of veterans with
GWI; this proportion was not statistically different from the proportion of positive LA identified in patients diagnosed with the other autoimmune conditions. The present findings add to the literature implicating autoimmune mechanisms in
GWIand point to the presence of prothrombotic antiphospholipid antibodies as a common contributing factor in
GWIand other autoimmune disorders. Furthermore, activation of the coagulation system suggests new potential avenues for treatment for LA-positive Gulf War veterans.
Human Connectome Project: heritability of brain volumes in young healthy adults
Synchronous neuronal interactions in rat hypothalamic culture: a novel model for the study of network dynamics in metabolic disorders
Human Leukocyte Antigen Alleles Prevent Metabolically-Induced Inflammation and Cerebrocortical Thinning in Gulf War Illness
permalinkJournal of Neurology & Neuromedicine - 2020-10-20Christova P, James L, Carpenter A, Lewis S, Engdahl B, Georgopoulos APIndependent lines of research have demonstrated that
GWIis associated with elevated inflammatory markers, metabolic disruptions, and alterations in brain morphometry. Possessing specific Class II
HLAalleles, on the other hand, has been shown to protect against
GWIand to be inversely associated with symptom severity in a dose-dependent manner. The aim of the present study was to evaluate the association between C-reactive protein (CRP), a marker of inflammation, body mass index (BMI), and brain morphometry in
GWIveterans with and without a protective
HLAallele. Sixty-three veterans with
GWIprovided blood samples for evaluation of CRP and
HLA, height and weight for calculating BMI, and underwent a 3T magnetic resonance imaging scan from which the volume, surface area, and cortical thickness of 68 cortical regions of interest (ROI) were determined. Results demonstrated that the CRP was highly significantly associated with BMI and cortical thinning in veterans lacking protective
HLAalleles but not in those possessing a protective
HLAallele. Given the role of
HLAin antibody production against foreign antigens, the findings suggest that persistent foreign antigens stemming from lack of immunogenetic protection against them contribute to inflammation, metabolic disruption, and cortical thinning in
GWI. The findings are discussed in terms of GW-related exposures that are known to result in inflammation.
C-Reactive Protein is Associated with Brain White Matter Anomalies in Gulf War Illness
permalinkJournal of Neurology & Neuromedicine - 2020-10-01Christova P, James L, Carpenter A, Lewis S, Johnson R, Engdahl B, Georgopoulos APIndependent lines of research have documented elevated peripheral inflammation and brain white matter alterations in
GWI. We recently documented an association of C-reactive protein (CRP), a marker of inflammation, and decreased fornix white matter integrity in
GWI. The aim of the present study was to extend those findings to evaluate the association between CRP and white matter anisotropy and diffusion throughout the brain in
GWI. Sixty-three veterans with
GWIprovided blood samples for evaluation of CRP and underwent a 3T magnetic resonance imaging scan from which fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD), and mean diffusivity (MD) were obtained. An additional index characterizing the shape of the diffusion ellipsoid, Ca, which reflects deviation from sphericity (or isotropy) was obtained. Results demonstrated that CRP was significantly associated with decreased FA and Ca and with increased RD and MD, but not AD. These findings documenting a highly significant association between peripheral inflammation and specific white matter alterations in
GWIare discussed in terms of
GWI-related exposures that may promote systemic inflammation and deleterious neural effects downstream
Shared Human Leukocyte Antigen Coverage in dementia and Parkinson's disease
HLAClass II DRB1 alleles that are protective or neutral with respect to dementia. Here we extend those findings to evaluate the association of the population frequency of
HLADRB1 alleles with the prevalence of dementia and Parkinson's disease in14 Continental Western European countries. Nine
HLADRB1 alleles were identified including four that are protective against dementia (DRB1*01:01, DRB1*04:01, DRB1*13:02, DRB1*15:01), three that are neutral (DRB1*03:01, DRB1*07:01, DRB1*08:01), and two susceptibility alleles (DRB1*11:01, DRB1*04:05). Results demonstrated that the population prevalence's of dementia and Parkinson's disease are highly correlated and that the association between the nine DRB1 alleles above and the population prevalence of dementia is highly overlapping with that of Parkinson's disease. These findings suggest a common
HLAClass II DRB1 profile. Given the diverse role of
HLAClass II alleles in protection from foreign antigens, autoimmunity, and, possibly, neuroprotection, the shared
HLAprofile between dementia and Parkinson's disease indicates that common immunogenetic mechanisms underlie the pathogenesis and manifestation of these diseases
Assessing Recovery from Mild Traumatic Brain Injury (Mtbi) using Magnetoencephalography : An Application of the Synchronous Neural Interactions Test
permalinkJournal of Neurology & Neuromedicine - 2020-09-03Thorpe D, Engdahl B, Leuthold A, Georgopoulos APMild traumatic brain injury (mTBI) affects 22% of U.S. service members returning from Afghanistan and Iraq. Its diagnosis is challenging due to the heterogeneous structural and functional alterations inflicted by diverse injury mechanisms. mTBI is diagnosed mainly based on history (trauma) and clinical evaluation, since conventional neuroimaging methods, such as magnetic resonance imaging (MRI) and computerized tomography (CT) of the brain, typically do not reveal clear abnormalities. Similarly, the assessment of recovery following mTBI relies exclusively on clinical evaluation, based on several criteria. With respect to brain function, we hypothesized that mTBI reflects disturbed dynamic interactions among neuronal populations, a disturbance not detectable by the aforementioned techniques. In a quest for an objective tool to detect the presence of mTBI and assess recovery from it, here we used
Magnetoencephalography, a modality highly suited to assess the dynamic functional status of the brain. Specifically, we used the
SNItest to evaluate functional brain status of 257 healthy ("control") veterans, 19 veterans with a clinical diagnosis of active mTBI ("a-mTBI"), and 18 veterans who suffered from mTBI and, at the time of testing, were deemed to have recovered from it ("r-mTBI"). A stepwise linear discriminant analysis (LDA) yielded 37
SNIpredictors that classified 100% correctly of all 257 control and 19 a-mTBI brains. We then used these predictors to classify the 18 r-mTBI brains to control or a-mTBI groups: 9 brains (50%) were classified as control, whereas the other 10 (50%) were classified as a-mTBI. These findings (a) document the power of
MEGto correctly detect a-mTBI, and (b) raise concerns regarding the validity of clinical assessment tools to pronounce recovery from mTBI. On the positive side, our results provide an objective brain-based continuum along which the status of a mTBI brain can be assessed. This measure, together with clinical evaluation, should appreciably reduce the uncertainty and considerably improve the quantification of recovery from mTBI, guiding further treatment.
Gulf War Illness: C-Reactive Protein is Associated with Reduction of the Volume of Hippocampus and Decreased Fractional Anisotropy of the Fornix
permalinkJournal of Neurology & Neuromedicine - 2020-08-11Christova P, James L, Carpenter A, Lewis S, Johnson R, Engdahl B, Georgopoulos APMemory and mood impairments are among the most commonly reported symptoms in veterans with
GWI, suggesting hippocampal involvement. Several studies have also documented evidence of inflammation in
GWI. The aim of the present study was to evaluate the association between C-reactive protein (CRP), a marker of inflammation, and hippocampal volume and microstructural alterations of its major output, the fornix. Sixty-three veterans with
GWIprovided blood samples for evaluation of CRP and underwent a 3T magnetic resonance imaging scan from which hippocampal volume and fornix fractional anisotropy (FA) were obtained. Results demonstrated that CRP was significantly and negatively associated with hippocampal volume and fornix FA in
GWI. Given the known closely interwoven associations between inflammation and neurodegeneration, it is possible that the effects we observed could be due to neurodegeneration, secondary to chronic neuroinflammation. Finally, given the known association of hippocampus to memory and mood disorders, our findings provide new insights into memory and mood alterations associated with
Behavioral-genetic associations in the Human Connectome Project
Anthrax Protective Antigen 63 (PA63): Toxic Effects in Neural Cultures and Role in Gulf War Illness
permalinkNeuroscience Insights - 2020-06-30Tsilibary EC, Souto EP, Kratzke M, James L, Engdahl B, Georgopoulos AP10.1177/2633105520931966Protective antigen (PA) 63 (PA63) is a protein derived from the PA83 component contained in the anthrax vaccine. The anthrax vaccine ("Biothrax") was administered together with other vaccines to Gulf War veterans, about 35% of whom later developed a multisymptom disease (
GWI]), with prominent neurological/cognitive/mood symptoms, among others. The disease has been traditionally attributed to exposures to toxic chemicals during the war but other factors could be involved, including vaccines received. Of these, the anthrax vaccine is the most toxic. Here, we assessed directly the PA63 toxin's harmful effects on cultured neuroblastoma 2A (N2A) cells with respect to cell spreading, process formation, apoptosis, and integrity of cell membrane, cytoskeleton, and mitochondria. We found that, when added in N2A cultures, PA63 toxin led to decreased cell spreading and cell aggregation, leading to apoptosis. The mechanisms of PA63-induced cell damage included compromised cell membrane permeability indicated by enhanced access of propidium iodide in cells. In addition, signaling pathways leading to organization of N2A cytoskeleton were negatively affected, as both actin and microtubular networks were compromised. Finally, the mitochondrial membrane potential was impaired in specific assays. Altogether, these alterations led to apoptosis as a collective toxic effect of PA63 which was substantially reduced by the concomitant addition of specific antibodies against PA63.
Vaccine-Induced Adverse Effects in Cultured Neuroblastoma 2A (N2A) Cells Duplicate Toxicity of Serum from Patients with Gulf War Illness and Are Prevented in the Presence of Specific Anti-Vaccine Antibodies
permalinkVaccines - 2020-05-18Tsilibary EC, Souto EP, Kratzke M, James L, Engdahl B, Georgopoulos AP10.3390/vaccines8020232GWI is a chronic disease of unknown etiology affecting over 200,000 veterans with symptoms including neurocognitive problems. We previously demonstrated
GWIserum toxicity on neural cell cultures manifested by compromised neural network function, decreased cell spreading, and enhanced cell apoptosis. These patients lacked six
HLAclass II alleles, resulting in an inability to form antibodies. Therefore, we hypothesized that
GWIpatients have vaccine-derived, persistent pathogens, which contribute to the development of the disease. Here, we examined whether individual vaccines were toxic in cultured N2A cells. Moreover, we used antibodies against each of the 20 vaccines administered to Gulf War (GW) veterans, to examine the effects of these antibodies on cell spreading and apoptosis in N2A cells. Antibodies against cholera toxin, hepatitis B, hemagglutinin H1N1, H3N2, and B from influenza A and B strains, measles, and Salmonella Typhi polysaccharide Vi had a remarkable protective effect on both cell spreading and apoptosis, whereas none of the other antibodies administered to GW veterans had an effect. The in vitro observed adverse effects of
GWIserum may be due in part to vaccine-derived pathogens, antibodies against which had a protective effect in N2A cell cultures.
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.
Tri-Allelic Human Leukocyte Antigen Protection Against Dementia
HLAalleles - DRB1*01:01 and DRB1*15:01 - alone and in combination with DRB1*13:02, on dementia prevalence in Continental Western Europe. Results indicated that the prevalence of dementia in 14 Continental Western European (CWE) countries significantly decreased exponentially with increasing frequency of any of the three alleles alone and in combination (P's < 0.001). When combined, the population frequency of the three alleles accounted for 67% of the variance in dementia prevalence. The combined frequency of DRB1*01:01, DRB1*13:02, and DRB1*15:01 was also significantly associated with dementia prevalence in those aged 65 years and older (P = 0.004) and with a change in dementia prevalence between 1990 and 2016 (P = 0.006). These findings, which document the protective effects of three common Class II HLA alleles on dementia prevalence in CWE, are discussed in terms of the role of HLA class II genes in pathogen elimination. More specifically, we hypothesize that dementia prevalence is higher for countries in which the population frequency of these protective alleles is low, prohibiting the successful elimination of pathogens that may play a causal role in dementia.
Anthrax and Gulf War Illness: Evidence for the Presence of Harmful Anthrax Antigen PA63 In the Serum of Veterans with GWI
permalinkJournal of Neurology & Neuromedicine - 2019-11-25Tsilibary EC, Souto EP, Kratzke M, James L, Engdahl B, Georgopoulos APGWI is a multisystem disorder of unknown etiology that has afflicted many veterans of the 1990-91 Gulf War who have sustained progressively worsening health since the war. Recent studies have demonstrated the presence of active inflammation in
GWIand, in addition, a positive association of the levels of C-reactive protein (CRP), an inflammatory marker, with
GWIsymptom severity. Moreover, we have shown that
GWIserum contains substances that are harmful to neural cultures', a detrimental effect that can be prevented by serum of healthy GW veterans and partially so by pooled human immunoglobulin G (IgG). Although possible exposure to environmental toxins in war theater has been traditionally blamed for
GWI6, the evidence above and the fact that the disease also afflicted nondeployed veterans, point to other causes, including the vaccines administered to GW veterans, such as the vaccine against anthrax. Here we present, for the first time, evidence indicating the presence of the harmful anthrax protective antigen PA63 in the serum of 15 veterans suffering from
GWI, as follows. First, we confirmed that the addition of
GWIserum to the culture had a detrimental effect, including decreased cell spreading and increased cell apoptosis, as reported previously. And second, we found that the concomitant addition of specific polyclonal or monoclonal antibodies against PA63 had a remarkable protective effect on N2A cultures, significantly ameliorating cell spreading and reducing cell apoptosis. These results document that the adverse effects of
GWIserum on neural cultures are due, in part, to persistent pathogens derived from the anthrax vaccine. We hypothesize that these anthrax pathogens persisted in the blood of the
GWIveterans tested because of inability of those veterans to make antibodies against them, probably due to lack of
HLAprotection. Finally, our findings point to a possible successful intervention in
GWIconsisting in neutralizing (by administering specific antibodies) and/or removing (by plasmapheresis) those harmful anthrax antigens.
In Silico Analysis of the Binding Affinities of Antigenic Epitopes of Vaccines Administered to Gulf War Veterans to Specific HLA Class II Alleles Protective for GWI
HLAclass II alleles that are protective for
GWI, namely DPB1*01:01, DPB1*06:01, DQB1*02:02, DRB1*01:01, DRB1*08:11, and DRB1*13:02. Since the function of
HLAclass II molecules is to connect with matching extracellular antigens of various pathogens (mostly viruses), as an initial step in the sequence of events leading to the development of antibodies against the matched antigen and its subsequent elimination, we hypothesized that
GWImay be due, in part, to the persistence of offending antigens which could not be eliminated. We further hypothesized that such antigens were contained in the 16 vaccines administered to GW veterans against adenovirus, anthrax, botulinum, cholera, diphtheria, hepatitis B, influenza A, Japanese encephalitis, measles, meningococcus, poliomyelitis, rabies, smallpox, tetanus, typhoid, yellow fever. This hypothesis predicts that antigens present in those vaccines should have a high affinity for matching with the 6
HLAclass II protective alleles above. Here we tested this prediction by using the Immune Epitope DataBase (IEDB7) to determine the ranked affinity of each one of the 6
GWIprotective alleles to the 10 most frequently assayed epitopes of each pathogen for which a vaccine was administered. We found that our 6
GWIprotective alleles above collectively covered all vaccine antigens except for rubella for which all alleles above showed low binding affinity. Affinity strength varied among antigen-allele pairs, with DRB1*01:01 and DRB1*13:02 showing overall higher affinities. These two alleles also had the highest binding affinities for the anthrax antigen contained in the anthrax vaccine administered to GW veterans. These findings document a good match between the 6
HLAprotective alleles above and the antigens contained in the GW vaccines, and support the fundamental assumption that the
GWIis mediated through the successful elimination of potentially harmful persistent antigens contained in those vaccines.
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.
Decades of Posttraumatic Stress Disorder and Gulf War Illnes Research: Driven to Discover Causes and New Therapies
Posttraumatic Stress Disorderand
A Two-Hit Model of the Biological Origin of Posttraumatic Stress Disorder
permalinkJournal of Mental Health and Clinical Psychology - 2018-10-01Georgopoulos AP, James L, Christova P, Engdahl BWe focus on the origin of
PTSD, on the meural mechanisms underlying its development. Specifically, we propose a two-hit model for
PTSDdevelopment, with the following components:
- the 1st hit is a neuroimmune challenge, as a preexisting condition
- the 2nd hit is intense glutamatergic neurotrasmission, induced by the traumatic event.
PTSDand maintains associated symptomatology, such as fear and avoidance