Negative association between neurovascular coupling and cortical gray matter volume during the lifespan.

Recent studies have established the moment-to-moment turnover of the blood-oxygen-level-dependent signal (TBOLD) at resting state as a key measure of local cortical brain function. Here, we sought to extend that line of research by evaluating TBOLD in 70 cortical areas with respect to corresponding brain volume, age, and sex across the lifespan in 1,344 healthy participants including 633 from the Human Connectome Project (HCP)-Development cohort (294 males and 339 females, age range 8-21 yr) and 711 healthy participants from HCP-Aging cohort (316 males and 395 females, 36-90 yr old). In both groups, we found that 1) TBOLD increased with age, 2) volume decreased with age, and 3) TBOLD and volume were highly significantly negatively correlated, independent of age. The inverse association between TBOLD and volume was documented in nearly all 70 brain areas and for both sexes, with slightly stronger associations documented for males. The strong correspondence between TBOLD and volume across age and sex suggests a common influence such as chronic neuroinflammation contributing to reduced cortical volume and increased TBOLD across the lifespan.NEW & NOTEWORTHY We report a significant negative association between resting functional magnetic resonance imaging (fMRI) blood-oxygen-level-dependent (BOLD) signal turnover (TBOLD) and cortical gray matter volume across the lifespan, such that TBOLD increased whereas volume decreased. We attribute this association to a hypothesized chronic, low-grade neuroinflammation, probably induced by various neurotropic pathogens, including human herpes viruses known to be dormant in the brain in a latent state and reactivated by stress, fever, and various environmental exposures, such as ultraviolet light.

Anthrax Vaccines in the 21st Century.

Vaccination against Bacillus anthracis is the best preventive measure against the development of deadly anthrax disease in the event of exposure to anthrax either as a bioweapon or in its naturally occurring form. Anthrax vaccines, however, have historically been plagued with controversy, particularly related to their safety. Fortunately, recent improvements in anthrax vaccines have been shown to confer protection with reduced short-term safety concerns, although questions about long-term safety remain. Here, we (a) review recent and ongoing advances in anthrax vaccine development, (b) emphasize the need for thorough characterization of current (and future) vaccines, (c) bring to focus the importance of host immunogenetics as the ultimate determinant of successful antibody production and protection, and (d) discuss the need for the systematic, active, and targeted monitoring of vaccine recipients for possible Chronic Multisymptom Illness (CMI).

Association between brain cancer immunogenetic profile and in silico immunogenicities of 11 viruses.

Several viruses including human herpes viruses (HHVs), human polyomavirus JCV, and human papilloma virus (HPV) have been implicated in brain cancer, albeit inconsistently. Since human leukocyte antigen (HLA) is centrally involved in the human immune response to viruses and has been implicated in brain cancer, we evaluated in silico the immunogenicity between 69 Class I HLA alleles with epitopes of proteins of 9 HHVs, JCV, and HPV with respect to a population-based HLA-brain cancer profile. We found that immunogenicity varied widely across HLA alleles with HLA-C alleles exhibiting the highest immunogenicity, and that immunogenicity scores were negatively associated with the population-based HLA-brain cancer profile, particularly for JCV, HHV6A, HHV5, HHV3, HHV8, and HHV7. Consistent with the role of HLA in foreign antigen elimination, the findings suggest that viruses with proteins of high HLA immunogenicity are eliminated more effectively and, consequently, less likely to cause brain cancer; conversely, the absence of highly immunogenic HLA may allow the viral antigens to persist, contributing to cancer.

Positive Association Between the Immunogenetic Human Leukocyte Antigen (HLA) Profiles of Multiple Sclerosis and Brain Cancer.

Previous research has documented elevated risk of brain cancer in patients with multiple sclerosis (MS). Separately, human leukocyte antigen (HLA) has been implicated in protection or susceptibility for both conditions. The aim of the current study was to assess a possible role of shared immunogenetic influence on risk of MS and brain cancer. We first identified an immunogenetic profile for each condition based on the covariance between the population frequency of 127 high-resolution HLA alleles and the population prevalence of each condition in 14 Continental Western European countries and then evaluated the correspondence between MS and brain cancer immunogenetic profiles. Also, since each individual carries 12 HLA alleles (2 × 6 genes), we estimated HLA protection and susceptibility for MS and brain cancer at the individual level. We found that the immunogenetic profiles of MS and brain cancer were highly correlated overall (P < .001) and across all 6 HLA genes with the strongest association observed for DRB1, followed by DQB1 and HLA-A. These findings of immunogenetic overlap between MS and brain cancer are discussed in light of the role of HLA in the immune system response to viruses and other foreign antigens.

Negative association between multiple sclerosis immunogenetic profile and in silico immunogenicities of 12 viruses.

Human Leukocyte Antigen (HLA) is involved in both multiple sclerosis (MS) and immune response to viruses. Here we investigated the virus-HLA immunogenicity (V-HLA) of 12 viruses implicated in MS with respect to 17 HLA Class I alleles positively associated to MS prevalence in 14 European countries. Overall, higher V-HLA immunogenicity was associated with smaller MS-HLA effect, with human herpes virus 3 (HHV3), JC human polyoma virus (JCV), HHV1, HHV4, HHV7, HHV5 showing the strongest association, followed by HHV8, HHV6A, and HHV6B (moderate association), and human endogenous retrovirus (HERV-W), HHV2, and human papilloma virus (HPV) (weakest association). These findings suggest that viruses with proteins of high HLA immunogenicity are eliminated more effectively and, consequently, less likely to be involved in MS.

Melanoma and Human Leukocyte Antigen (HLA): Immunogenicity of 69 HLA Class I Alleles With 11 Antigens Expressed in Melanoma Tumors.

Host immunogenetics play a critical role in the human immune response to melanoma, influencing both melanoma prevalence and immunotherapy outcomes. Beneficial outcomes that stimulate T cell response hinge on binding affinity and immunogenicity of human leukocyte antigen (HLA) with melanoma antigen epitopes. Here, we use an in silico approach to characterize binding affinity and immunogenicity of 69 HLA Class I human leukocyte antigen alleles to epitopes of 11 known melanoma antigens. The findings document a significant proportion of positively immunogenic epitope-allele combinations, with the highest proportions of positive immunogenicity found for the Q13072/BAGE1 melanoma antigen and alleles of the HLA B and C genes. The findings are discussed in terms of a personalized precision HLA-mediated adjunct to immune checkpoint blockade immunotherapy to maximize tumor elimination.

Risk assessment of substance use disorders based on the human leukocyte antigen (HLA).

Substance use disorders (SUDs) are common and costly conditions that are partially attributable to genetic factors. In light of immune system influences on neural and behavioral aspects of addiction, the present study evaluated the influence of genes involved in the human immune response, human leukocyte antigen (HLA), on SUDs. We used an immunogenetic epidemiological approach to evaluate associations between the population frequencies of 127 HLA alleles and the population prevalences of six SUDs (alcohol, amphetamine, cannabis, cocaine, opioid, and "other" dependence) in 14 countries of Continental Western Europe to identify immunogenetic profiles of each SUD and evaluate their associations. The findings revealed two primary groupings of SUDs based on their immunogenetic profiles: one group comprised cannabis and cocaine, whereas the other group comprised alcohol, amphetamines, opioids, and "other" dependence. Since each individual possesses 12 HLA alleles, the population HLA-SUD scores were subsequently used to estimate individual risk for each SUD. Overall, the findings highlight similarities and differences in immunogenetic profiles of SUDs that may influence the prevalence and co-occurrence of problematic SUDs and may contribute to assessment of SUD risk of an individual on the basis of their HLA genetic makeup.

Schizophrenia, Human Leukocyte Antigen (HLA), and Herpes Viruses: Immunogenetic Associations at the Population Level.

Several factors have been implicated in schizophrenia (SZ), including human herpes viruses (HHV) and the adaptive immunity Human Leukocyte Antigen (HLA) genes. Here we investigated these issues in 2 complementary ways. In one analysis, we evaluated SZ-HLA and HHV-HLA associations at the level of a single allele by computing (a) a SZ-HLA protection/susceptibility (P/S) score based on the covariance between SZ and 127 HLA allele prevalences in 14 European countries, (b) estimating in silico HHV-HLA best binding affinities for the 9 HHV strains, and (c) evaluating the dependence of P/S score on HHV-HLA binding affinities. These analyses yielded (a) a set of 127 SZ-HLA P/S scores, varying by >200× (maximum/minimum), which could not be accounted for by chance, (b) a set of 127 alleles × 9 HHV best-estimated affinities, varying by >600×, and (c) a set of correlations between SZ-HLA P/S scores and HHV-HLA binding which indicated a prominent role of HHV1. In a subsequent analysis, we extended these findings to the individual person by taking into account the fact that every individual carries 12 HLA alleles and computed (a) the average SZ-HLA P/S scores of 12 randomly chosen alleles (2 per gene), an indicator of HLA-based SZ P/S for an individual, and (b) the average of the corresponding HHV estimated affinities for those alleles, an indicator of overall effectiveness of HHV-HLA binding. We found (a) that HLA protection for SZ was significantly more prominent than susceptibility, and (b) that protective SZ-HLA scores were associated with higher HHV-HLA binding affinities, indicating that HLA binding and subsequent elimination of several HHV strains may confer protection against schizophrenia.

Dependence of cognitive ability on synchronous neural interactions determined by magnetoencephalography.

Previous studies have shown that synchronous neural interactions (SNIs) underlying healthy brain function can be readily distinguished from neural anomalies associated with diseases including dementia; however, it is imperative to identify biomarkers that facilitate early identification of individuals at risk for cognitive decline before the onset of clinical symptoms. Here, we evaluated whether variation in brain function, controlling for age, corresponds with subtle decrements in cognitive performance in cognitively healthy women. A total of 251 women (age range 24-102 yr) who performed above established cutoffs on the Montreal cognitive assessment (MoCA) also underwent a task-free magnetoencephalography scan from which SNIs were computed. The results demonstrated that increased SNI was significantly associated with decreased cognitive performance (r2 = 0.923, P = 0.009), controlling for age. Compared with the lowest performers with normal cognition (MoCA = 26), SNI of the highest performers (MoCA = 30) was associated with decorrelation primarily in the right anterior temporal cortex region, with additional (weaker) foci in left anterior temporal cortex, right posterior temporal cortex, and cerebellum. The findings highlight the relevance of neural network decorrelation on cognitive functioning and suggest that subtle increases in SNI may presage future cognitive impairment.NEW & NOTEWORTHY This study in cognitively healthy women showed that decreased cognitive performance is associated with increased neural network correlations, particularly involving the temporal cortices. As healthy brain function relies on dynamic neural network communication, these findings suggest that subtle increases in correlated neural network activity may be a useful early indicator of decrements in cognitive function.

Human Leukocyte Antigen (HLA) Modulates the Dependence on Age of the Variability of Synchronous Neural Interactions.

Recent evidence documented a protective effect of Class II human leukocyte antigen (HLA) DRB1*13 on brain health across the lifespan including evidence of reduced neural network variability relative to non-carriers. Here, in an extension of those findings, we evaluated the influence of a large number of Class I and Class II HLA alleles on aging-related changes in neural network variability. Cognitively healthy women (N = 178) ranging in age from 28 to 99 years old underwent a magnetoencephalography scan from which neural network variability was calculated and provided a blood sample from which HLA and apolipoprotein E (ApoE) genotype were determined. The primary analyses assessed the dependence of network variability on age in carriers of a specific HLA allele compared to non-carriers. Effects were considered protective if there was a significant increase of network variability with age in the absence of a given HLA allele but not in its presence, and were considered to confer susceptibility if the converse was documented; HLA alleles that did not influence the dependence of network variability on age in their presence or absence were considered neutral. Of 50 alleles investigated, 22 were found to be protective, 7 were found to confer susceptibility, and 21 were neutral. The frequencies of those 50 alleles were not associated significantly with ApoE genotype. The findings, which document the influence of HLA on age-related brain changes and highlight the role of HLA in healthy brain function, are discussed in terms of the role of HLA in the human immune response to foreign antigens.

Immunogenetic Profiles and Associations of Breast, Cervical, Ovarian, and Uterine Cancers.

It is increasingly recognized that the human immune response influences cancer risk, progression, and survival; consequently, there is growing interest in the role of human leukocyte antigen (HLA), genes that play a critical role in initiating the immune response, on cancer. Recent evidence documented clustering of cancers based on immunogenetic profiles such that breast and ovarian cancers clustered together as did uterine and cervical cancers. Here we extend that line of research to evaluate the HLA profile of those 4 cancers and their associations. Specifically, we evaluated the associations between the frequencies of 127 HLA alleles and the population prevalences of breast, ovarian, cervical, and uterine cancer in 14 countries in Continental Western Europe. Factor analysis and hierarchical clustering were used to evaluate groupings of cancers based on their immunogenetic profiles. The results documented highly similar immunogenetic profiles for breast and ovarian cancers that were characterized predominantly by protective HLA effects. In addition, highly similar immunogenetic profiles for cervical and uterine cancers were observed that were, conversely, characterized by susceptibility effects. In light of the role of HLA in host immune system protection against non-self antigens, these findings suggest that certain cancers may be associated with similar contributory factors such as viral oncoproteins or neoantigens.

Immunogenetics of posttraumatic stress disorder (PTSD) in women veterans.

Posttraumatic stress disorder (PTSD) is a debilitating psychiatric condition that is associated with concomitant immune system dysfunction. Here we evaluated the influence of genes involved in the human immune response, Human Leukocyte Antigen (HLA), on lifetime PTSD in primarily Caucasian women veterans. High-resolution HLA genotyping was completed for 372 participants. We assessed differences in HLA makeup between Control (n = 277) and lifetime PTSD (n = 95) groups. HLA was found to have a significant overall effect on lifetime PTSD occurrence (P < 0.00001). Of the 192 alleles identified in this sample, the frequencies of 15 alleles significantly differed between groups. Two alleles - HLA-A*02:01 and DPB1*04:01 -occurred more frequently in controls, presumably indicating protective effects. Thirteen alleles (6 Class I, 7 Class II) occurred more frequently in the lifetime PTSD group, presumably indicating susceptibility effects. In analysis evaluating the effect of the combined presence in individual participants of a protective allele and a susceptibility allele, the presence of a protective allele neutralized the effect of the susceptibility alleles. These findings, which add to the nascent literature on immunogenetics of PTSD, are discussed in terms of the evolutionary role of HLA in host protection against foreign antigens.

Reply to the Letter to the Editor by Sipila, Jussi.

This a Reply to the Letter to the Editor by Sipila, Jussi regarding our article titled: James LM, Georgopoulos AP. High Correlations Among Worldwide Prevalences of Dementias, Parkinson's Disease, Multiple Sclerosis, and Motor Neuron Diseases Indicate Common Causative Factors. Neurosci Insights. 2022 Aug 8;17:26331055221117598. doi: 10.1177/26331055221117598.

The brain landscape of the two-hit model of posttraumatic stress disorder.

The neurophysiological mechanisms underlying the development of posttraumatic stress disorder (PTSD) are poorly understood. Here we test a proposal that PTSD symptoms reflect fixed, highly correlated neural networks resulting from massive engagement of sensory inputs and the sequential involvement of those projections to limbic areas. Three-tesla functional magnetic resonance imaging (fMRI) data were acquired at rest in 15 veterans diagnosed with PTSD and 21 healthy control veterans from which zero-lag cross correlations between 50 brain areas (N = 1,225 pairs) were computed and analyzed. The brain areas were assigned to tiers based on the neurocircuitry of successively converging sensory pathways proposed by Jones and Powell (Jones EG, Powell TP. Brain 93: 793-820, 1970). The primary analyses assessed normalized proportional differences in cross correlation strength within and across tiers in veterans with PTSD and control veterans. Compared with control veterans, cross correlation strength was higher in veterans with PTSD, within and across tiers of areas involved in processing sensory inputs, and systematically increased from sensory processing areas to limbic areas. The functional relevance of this hypercorrelation was further documented by the finding that the severity of self-reported PTSD symptomatology was positively associated with higher neural correlations.NEW & NOTEWORTHY The neurophysiological mechanisms underlying the development of PTSD are poorly understood. Here we document that massive engagement of sensory modalities during trauma exposure leads to fixed, hypercorrelated frontal, parietal, temporal, and limbic networks, reflecting the successive integration of salient sensory inputs along the framework of Jones and Powell.

At the Root of 3 "Long" Diseases: Persistent Antigens Inflicting Chronic Damage on the Brain and Other Organs in Gulf War Illness, Long-COVID-19, and Chronic Fatigue Syndrome.

Several foreign antigens such as those derived from viruses and bacteria have been linked to long-term deleterious effects on the brain and other organs; yet, health outcomes subsequent to foreign antigen exposure vary depending in large part on the host's immune system, in general, and on human leukocyte antigen (HLA) composition, in particular. Here we first provide a brief description of 3 conditions characterized by persistent long-term symptoms, namely long-COVID-19, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and Gulf War Illness (GWI), followed by a brief overview of the role of HLA in the immune response to foreign antigens. We then discuss our Persistent Antigen (PA) hypothesis and highlight associations between antigen persistence due to HLA-antigen incongruence and chronic health conditions in general and the 3 "long" diseases above in particular. This review is not intended to cover the breadth and depth of symptomatology of those diseases but is specifically focused on the hypothesis that the presence of persistent antigens underlies their pathogenesis.

High Correlations Among Worldwide Prevalences of Dementias, Parkinson's Disease, Multiple Sclerosis, and Motor Neuron Diseases Indicate Common Causative Factors.

Dementia, Parkinson's disease, multiple sclerosis, and motor neuron diseases cause significant disability and mortality worldwide. Although the etiology of these diseases is unknown, highly correlated disease prevalences would indicate the involvement of common etiologic factors. Here we used published epidemiological data in 195 countries worldwide to investigate the possible intercorrelations among the prevalences of these diseases. All analyses were carried out using nonparametric statistics on rank-transformed data to assure the robustness of the results. We found that all 6 pairwise correlations among the prevalences of the 4 diseases were very high (>.9, P < .001). A factor analysis (FA) yielded only a single component which comprised all 4 disease prevalences and explained 96.3% of the variance. These findings indicate common etiologic factor(s). Next, we quantified the contribution of 3 country-specific factors (population size, life expectancy, latitude) to the common grouping of prevalences by estimating the reduction in total FA variance explained when the effect of these factors was eliminated by using the prevalence residuals from a linear regression where theses factor were covariates. FA of these residuals yielded again only a single component comprising all 4 diseases which explained 71.5% of the variance, indicating that the combined contribution of population size, life expectancy and latitude accounted for 96.3% - 71.5% = 24.8% of the FA variance explained. The fact that the 3 country-specific factors above accounted for only 24.8% of the FA variance explained by the original (ranked) disease prevalences, in the presence still of a single grouping factor, strongly indicates the operation of other unknown factors jointly contributing to the pathogenesis of the 4 diseases. We discuss various possible factors involved, with an emphasis on biologic pathogens (viruses, bacteria) which have been implicated in the pathogenesis of these diseases in previous studies.

The dynamic shaping of local cortical circuitry by sex and age, and its relation to pattern comparison processing speed.

Previous resting-state functional magnetic resonance imaging (fMRI) studies have shown that the strength of local neural interactions decreases with distance. Here, we extend that line of research to evaluate effects of sex and age on local cortical circuitry in six cortical areas (superior frontal, precentral, postcentral, superior parietal, inferior parietal, and lateral occipital) using data acquired from 1,054 healthy young adults who participated in the Human Connectome Project. We confirmed previous findings that the strength of zero-lag correlations between prewhitened, resting-state, blood level oxygenation-dependent (BOLD) fMRI time series decreased with distance locally and documented that the rate of decrease with distance (spatial steepness) 1) was progressively lower from anterior to posterior areas, 2) was greater in women, especially in anterior areas, 3) increased with age, particularly for women, 4) was significantly correlated with percent inhibition, and 5) was positively and highly significantly correlated with pattern comparison processing speed (PCPS). A hierarchical tree clustering analysis of this dependence of PCPS on spatial steepness revealed a differential organization in processing that information between the two hemispheres, namely, a more independent vs. a more integrative processing in the left and right hemispheres, respectively. These findings document sex and age differences in dynamic local cortical interactions and provide evidence that spatial sharpening of these interactions may underlie cognitive processing speed differently organized in the two hemispheres.NEW & NOTEWORTHY Sex and age significantly affect shaping of local cortical interactions that are more limited in women and older brains. The net result is an increase in local spatial steepness of interactions, leading to a reduction of overlap among local ensembles and, hence, a more efficient information processing and an increase in the number of independent local cortical "processors." Remarkably, cognitive processing speed was positively associated with local spatial steepness, in keeping with the reasoning earlier.

MEG neural signature of sexual trauma in women veterans with PTSD.

Previous research has documented the utility of synchronous neural interactions (SNI) in classifying women veterans with and without posttraumatic stress disorder (PTSD) and other trauma-related outcomes based on functional connectivity using magnetoencephalography (MEG). Here, we extend that line of research to evaluate trauma-specific PTSD neural signatures with MEG in women veterans. Participants completed diagnostic interviews and underwent a task-free MEG scan from which SNI was computed. Thirty-five women veterans were diagnosed with PTSD due to sexual trauma and sixteen with PTSD due to non-sexual trauma. Strength of SNI was compared in women with and without sexual trauma, and linear discriminant analysis was used to classify the brain patterns of women with PTSD due to sexual trauma and non-sexual trauma. Comparison of SNI strength between the two groups revealed widespread hypercorrelation in women with sexual trauma relative to those without sexual trauma. Furthermore, using SNI, the brains of participants were classified as sexual trauma or non-sexual trauma with 100% accuracy. These findings bolster evidence supporting the utility of task-free SNI and suggest that neural signatures of PTSD are trauma-specific.

Immunogenetic clustering of 30 cancers.

Human leukocyte antigen (HLA) genes have been implicated in cancer risk and shared heritability of different types of cancer. In this immunogenetic epidemiological study we first computed a Cancer-HLA profile for 30 cancer types characterized by the correlation between the prevalence of each cancer and the population frequency of 127 HLA alleles, and then used multidimensional scaling to evaluate the possible clustering of those Cancer-HLA associations. The results indicated the presence of three clusters, broadly reflecting digestive-skin-cervical cancers, reproductive and endocrine systems cancers, and brain and androgen-associated cancers. The clustering of cancer types documented here is discussed in terms of mechanisms underlying shared Cancer-HLA associations.

BOLD turnover in task-free state: variation among brain areas and effects of age and human leukocyte antigen (HLA) DRB1*13.

Blood oxygen level dependent (BOLD) signal in functional magnetic resonance imaging (fMRI) is frequently used as a proxy for underlying neural activity. Although this is a plausible assumption for experiments where a task is performed, it may not hold to the same degree for conditions of fMRI recording in a task-free, "resting" state where neural synaptic events are weak and, hence, neurovascular coupling and endothelial vascular factors become more prominent (Hillman Annu Rev Neurosci 37:161-181, 2014, 10.1146/annurev-neuro-071013-014111). Here we investigated the magnitude of change of BOLD in consecutive samples over the acquisition time period (turnover of BOLD, "TBOLD") by first-order differencing of single-voxel BOLD time series acquired in 70 areas of the cerebral cortex of 57 cognitively healthy women in a task-free resting state. More specifically, we evaluated (a) the variation of TBOLD among different cortical areas, (b) its dependence on age, and (c) its dependence on the presence (or absence) of the neuroprotective Human Leukocyte Antigen (HLA) gene DRB1*13 (DRB1*13:02 and DRB1*13:01). We found that TBOLD (a) varied substantially by 2.2 × among cortical areas, being highest in parahippocampal and entorhinal areas and lowest in parietal-occipital areas, (b) was significantly reduced in DRB1*13 carriers across cortical areas (from ~ 15% reduction in orbitofrontal cortex to 2% reduction in cuneus), and (c) increased with age in noncarriers of DRB1*13 but decreased with age in DRB1*13 carriers. These findings document significant dependencies of TBOLD on cortical area location, HLA DRB1*13 and age.