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.
Neuroscience Insights - 2022-10-26

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.

Shared Human Leukocyte AntigenHuman Leukocyte Antigen (HLA)Genes that are located in the Major Histocompatibility Complex (MHC) of chromosome 6 and play a central role in immune recognition. Most investigations of association of HLA to various diseases have focused on evaluating HLA allele frequencies in diseases of interest, as compared to the general, healthy population. Such studies have demonstrated HLA involvement with cancer, autoimmune, and in- fectious diseases. HLA Class I proteins (HLA-A, B, C) are expressed on all nucleated cells and present peptides from endogenous proteins to cytotoxic T lymphocytes engaged in immune surveillance. HLA Class II proteins (HLA-DRB1, DRB3/4/5, DQB1, DPB1) are expressed on antigen-presenting cells and present peptides derived from exogenous proteins to CD4+helper T cells. A previous study of Gulf War syndrome in 27 veterans found that HLA DRB1*15 was more prevalent in cases than controls with an odds ratio of 1.66, although this association was not statistically significant. Coverage in dementia and Parkinson's disease

Dementia and Parkinson's disease are the two most common age-related neurodegenerative conditions. Recent studies have identified Human Leukocyte AntigenHuman Leukocyte Antigen (HLA)Genes that are located in the Major Histocompatibility Complex (MHC) of chromosome 6 and play a central role in immune recognition. Most investigations of association of HLA to various diseases have focused on evaluating HLA allele frequencies in diseases of interest, as compared to the general, healthy population. Such studies have demonstrated HLA involvement with cancer, autoimmune, and in- fectious diseases. HLA Class I proteins (HLA-A, B, C) are expressed on all nucleated cells and present peptides from endogenous proteins to cytotoxic T lymphocytes engaged in immune surveillance. HLA Class II proteins (HLA-DRB1, DRB3/4/5, DQB1, DPB1) are expressed on antigen-presenting cells and present peptides derived from exogenous proteins to CD4+helper T cells. A previous study of Gulf War syndrome in 27 veterans found that HLA DRB1*15 was more prevalent in cases than controls with an odds ratio of 1.66, although this association was not statistically significant. Class 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 HLAHuman Leukocyte Antigen (HLA)Genes that are located in the Major Histocompatibility Complex (MHC) of chromosome 6 and play a central role in immune recognition. Most investigations of association of HLA to various diseases have focused on evaluating HLA allele frequencies in diseases of interest, as compared to the general, healthy population. Such studies have demonstrated HLA involvement with cancer, autoimmune, and in- fectious diseases. HLA Class I proteins (HLA-A, B, C) are expressed on all nucleated cells and present peptides from endogenous proteins to cytotoxic T lymphocytes engaged in immune surveillance. HLA Class II proteins (HLA-DRB1, DRB3/4/5, DQB1, DPB1) are expressed on antigen-presenting cells and present peptides derived from exogenous proteins to CD4+helper T cells. A previous study of Gulf War syndrome in 27 veterans found that HLA DRB1*15 was more prevalent in cases than controls with an odds ratio of 1.66, although this association was not statistically significant. DRB1 alleles with the prevalence of dementia and Parkinson's disease in14 Continental Western European countries. Nine HLAHuman Leukocyte Antigen (HLA)Genes that are located in the Major Histocompatibility Complex (MHC) of chromosome 6 and play a central role in immune recognition. Most investigations of association of HLA to various diseases have focused on evaluating HLA allele frequencies in diseases of interest, as compared to the general, healthy population. Such studies have demonstrated HLA involvement with cancer, autoimmune, and in- fectious diseases. HLA Class I proteins (HLA-A, B, C) are expressed on all nucleated cells and present peptides from endogenous proteins to cytotoxic T lymphocytes engaged in immune surveillance. HLA Class II proteins (HLA-DRB1, DRB3/4/5, DQB1, DPB1) are expressed on antigen-presenting cells and present peptides derived from exogenous proteins to CD4+helper T cells. A previous study of Gulf War syndrome in 27 veterans found that HLA DRB1*15 was more prevalent in cases than controls with an odds ratio of 1.66, although this association was not statistically significant. DRB1 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 HLAHuman Leukocyte Antigen (HLA)Genes that are located in the Major Histocompatibility Complex (MHC) of chromosome 6 and play a central role in immune recognition. Most investigations of association of HLA to various diseases have focused on evaluating HLA allele frequencies in diseases of interest, as compared to the general, healthy population. Such studies have demonstrated HLA involvement with cancer, autoimmune, and in- fectious diseases. HLA Class I proteins (HLA-A, B, C) are expressed on all nucleated cells and present peptides from endogenous proteins to cytotoxic T lymphocytes engaged in immune surveillance. HLA Class II proteins (HLA-DRB1, DRB3/4/5, DQB1, DPB1) are expressed on antigen-presenting cells and present peptides derived from exogenous proteins to CD4+helper T cells. A previous study of Gulf War syndrome in 27 veterans found that HLA DRB1*15 was more prevalent in cases than controls with an odds ratio of 1.66, although this association was not statistically significant. Class II DRB1 profile. Given the diverse role of HLAHuman Leukocyte Antigen (HLA)Genes that are located in the Major Histocompatibility Complex (MHC) of chromosome 6 and play a central role in immune recognition. Most investigations of association of HLA to various diseases have focused on evaluating HLA allele frequencies in diseases of interest, as compared to the general, healthy population. Such studies have demonstrated HLA involvement with cancer, autoimmune, and in- fectious diseases. HLA Class I proteins (HLA-A, B, C) are expressed on all nucleated cells and present peptides from endogenous proteins to cytotoxic T lymphocytes engaged in immune surveillance. HLA Class II proteins (HLA-DRB1, DRB3/4/5, DQB1, DPB1) are expressed on antigen-presenting cells and present peptides derived from exogenous proteins to CD4+helper T cells. A previous study of Gulf War syndrome in 27 veterans found that HLA DRB1*15 was more prevalent in cases than controls with an odds ratio of 1.66, although this association was not statistically significant. Class II alleles in...