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Biomedical subjects

R H Yolken

Publications and source records attributed to R H Yolken.

At least 19 recordsLinked to original sources
PubMed2006

Brain morphological changes associated with exposure to HSV1 in first-episode schizophrenia.

Infectious agents have been proposed as one of the risk factors for schizophrenia. However, the data on the association of infectious agents with in vivo brain changes are scant. We evaluated the association of serological evidence of exposure to herpes simplex virus 1 (HSV1) with in vivo brain structural variations among first-episode antipsychotic-naive schizophrenia/schizoaffective disorder patients and control subjects. We assayed HSV1 immunoglobulin G (IgG) antibody in serum samples from 30 patients and 44 healthy subjects and obtained structural magnetic resonance imaging scans from the same individuals. There were proportionately more patients with elevated HSV1 antibody ratios than healthy comparison subjects (chi2=3.98, 1 df, P=0.046) and patients had significantly higher HSV1 IgG antibody ratios compared with healthy subjects. Using optimized voxel-based morphometry, we examined diagnosis by HSV1 serological status interaction followed by within- and between-group comparison across the serological status. We observed a diagnosis by HSV1 serological status interaction and a significant main effect of HSV1 serological status in the prefrontal gray matter. Patients exposed to HSV1 had decreased gray matter in Brodmann area 9 (dorsolateral prefrontal cortex) and 32 (anterior cingulate cortex) compared with patients without serological evidence of exposure to HSV1. HSV1-associated differences in brain structure were not detected among healthy subjects. These findings suggest that HSV1 exposure in schizophrenia is associated with specific regional gray matter differences that may not be attributable to medications, illness chronicity or comorbid substance use. This study provides suggestive evidence for a link between HSV1 exposure and some of the cerebral morphological changes often reported in schizophrenia.

Adolescent↗
PubMed2006

Changes in region- and cell type-specific expression patterns of neutral amino acid transporter 1 (ASCT-1) in the anterior cingulate cortex and hippocampus in schizophrenia, bipolar disorder and major depression.

Although, the pathogenetic mechanisms of schizophrenia, bipolar disorder, and major depression are not clearly understood, various neurotransmitter systems are reported to have altered expression patterns of their receptor and transporter proteins. Changes in the expression of the neutral amino acid transporter 1 (ASCT-1) protein in the anterior cingulate gyrus and the hippocampus were investigated using immunohistochemistry and western blotting. A significant decrease in ASCT-1 immunoreactivity in neurons in the cingulate cortex as well as astrocytes of the white matter was seen in schizophrenia. In bipolar disorder and major depression, similar results were seen for neurons. In the hippocampus, there was a striking loss of immunoreactivity on astrocytes, neurons and interneurons in multiple regions in schizophrenia and bipolar disorder, while only minor changes were seen in major depression. The altered expression of ASCT-1 in neurons and astrocytes reflects profound changes in glutamatergic neurotransmission and highlights a significant role of astrocytes in the pathophysiology of neurotransmission in these major psychiatric disorders.

Adult↗
PubMed2005

Psychopathology in first-episode schizophrenia and antibodies to Toxoplasma gondii.

OBJECTIVE: Environmental factors such as infectious agents may contribute to the psychopathology and aetiology of schizophrenia. Toxoplasma gondii (TG) is a candidate infectious agent as it is known to replicate within the human central nervous system and to alter behaviour in experimental animals. METHOD: The relationship between antibodies to TG and psychopathological symptoms was examined in 34 first-episode patients with schizophrenia. RESULTS: Results of regression analyses revealed that symptoms on admission, predictors of outcome, age and family history of psychiatric disease influenced the levels of antibodies to TG. CONCLUSIONS: These results indicate that TG infections may play a role in the clinical manifestation of psychopathology in a subgroup of patients with schizophrenia.

Adolescent↗
PubMed2004

Mitochondrial dysfunction in schizophrenia: evidence for compromised brain metabolism and oxidative stress.

The etiology and pathophysiology of schizophrenia remain unknown. A parallel transcriptomics, proteomics and metabolomics approach was employed on human brain tissue to explore the molecular disease signatures. Almost half the altered proteins identified by proteomics were associated with mitochondrial function and oxidative stress responses. This was mirrored by transcriptional and metabolite perturbations. Cluster analysis of transcriptional alterations showed that genes related to energy metabolism and oxidative stress differentiated almost 90% of schizophrenia patients from controls, while confounding drug effects could be ruled out. We propose that oxidative stress and the ensuing cellular adaptations are linked to the schizophrenia disease process and hope that this new disease concept may advance the approach to treatment, diagnosis and disease prevention of schizophrenia and related syndromes.

Brain↗
PubMed2001

Retroviral RNA identified in the cerebrospinal fluids and brains of individuals with schizophrenia.

Schizophrenia is a serious brain disease of uncertain etiology. A role for retroviruses in the etiopathogenesis of some cases of schizophrenia has been postulated on the basis of clinical and epidemiological observations. We found sequences homologous to retroviral pol genes in the cell-free cerebrospinal fluids (CSFs) of 10 of 35 (29%) individuals with recent-onset schizophrenia or schizoaffective disorder. Retroviral sequences also were identified in the CSFs of 1 of 20 individuals with chronic schizophrenia. However, retroviral sequences were not identified in any of the CSFs obtained from 22 individuals with noninflammatory neurological diseases or from 30 individuals without evidence of neurological or psychiatric diseases (chi(2) = 19.25, P < 0.001). The nucleotide sequences identified in the CSFs of the individuals with schizophrenia or schizoaffective disorder were related to those of the human endogenous retroviral (HERV)-W family of endogenous retroviruses and to other retroviruses in the murine leukemia virus genus. Transcription of RNA homologous to members of the HERV-W family of retroviruses also was found to be up-regulated differentially in the frontal cortex regions of brains obtained postmortem from individuals with schizophrenia, as compared with corresponding tissue from individuals without psychiatric diseases. The transcriptional activation of certain retroviral elements within the central nervous system may be associated with the development of schizophrenia in at least some individuals. The further characterization of retroviral elements within the central nervous system of individuals with schizophrenia might lead to improved methods for the diagnosis and management of this disorder.

Adult↗
PubMed2001

Antibodies to Toxoplasma gondii in individuals with first-episode schizophrenia.

We employed enzyme immunoassay (EIA) and Western blotting techniques to measure the level of antibodies to Toxoplasma gondii proteins in serum samples from 38 individuals undergoing their first episode of schizophrenia and from a group of matched control subjects. We found that the individuals with first-episode schizophrenia had significantly increased levels of IgG, IgM, and IgA class antibodies to Toxoplasma proteins, as compared with the control subjects.

Adult↗
PubMed2001

Maternal infections and subsequent psychosis among offspring.

BACKGROUND: We tested the hypothesis that maternal infections during pregnancy are associated with the subsequent development of schizophrenia and other psychoses in adulthood. METHODS: We conducted a nested case-control study of 27 adults with schizophrenia and other psychotic illnesses and 54 matched unaffected control subjects (matched for sex, ethnicity, and date of birth) from the Providence, RI, cohort of the Collaborative Perinatal Project. We retrieved stored blood samples that had been obtained from these mothers at the end of pregnancy. These samples were analyzed for total class-specific immunoglobulins and for specific antibodies directed at recognized perinatal pathogens capable of affecting brain development. RESULTS: Maternal levels of IgG and IgM class immunoglobulins before the mothers were delivered of their neonates were significantly elevated among the case series (t = 3.06, P =.003; t = 2.93, P =.004, respectively, for IgG and IgM immunoglobulin-albumin ratios). Secondary analyses indicated a significant association between maternal antibodies to herpes simplex virus type 2 glycoprotein gG2 and subsequent psychotic illness (matched t test = 2.43, P =.02). We did not find significant differences between case and control mothers in the serum levels of IgA class immunoglobulins, or in specific IgG antibodies to herpes simplex virus type 1, cytomegalovirus, Toxoplasma gondii, rubella virus, human parvovirus B19, Chlamydia trachomatis, or human papillomavirus type 16. CONCLUSIONS: The offspring of mothers with elevated levels of total IgG and IgM immunoglobulins and antibodies to herpes simplex virus type 2 are at increased risk for the development of schizophrenia and other psychotic illnesses in adulthood.

Albumins↗
PubMed2001

Maternal cytokine levels during pregnancy and adult psychosis.

We investigated levels of maternal cytokines in late pregnancy in relation to the subsequent development of adult schizophrenia and other psychoses in their offspring. The sample included the mothers of 27 adults with schizophrenia and other psychotic illnesses and 50 matched unaffected controls from the Providence cohort of the Collaborative Perinatal Project. Serum samples were analyzed for interleukin 1 beta (IL-1-beta), interleukin 2 (IL-2), interleukin 6 (IL-6), interleukin 8 (IL-8), and tumor necrosis factor alpha (TNF-alpha) by enzyme immunoassay. Maternal levels of TNF-alpha were significantly elevated among the case series (t = 2.22, p =.04), with evidence of increasing odds of psychosis in relation to higher cytokine levels. We did not find significant differences between case and control mothers in the serum levels of IL-1, IL-2, IL-6, or IL-8. These data support previous clinical investigations reporting maternal infections during pregnancy as a potential risk factor for psychotic illness among offspring.

Adult↗
PubMed2001

Immunohistochemical localization of phosphorylated glial fibrillary acidic protein in the prefrontal cortex and hippocampus from patients with schizophrenia, bipolar disorder, and depression.

Increasingly, abnormalities of glial cell function have been implicated in pathological studies of the major mental illnesses (schizophrenia, bipolar disorder, and major depression). In a recent proteomic study, four isoforms of astrocytic glial fibrillary acidic protein (GFAP) were decreased in one or more of these diseases. In the current study, we sought to determine the immunohistochemical localization of phosphorylated GFAP (pGFAP) in the prefrontal cortex and hippocampus and to describe possible disease-related changes in the distribution of pGFAP containing astrocytes. In the prefrontal cortex, interlaminar astrocytes in layer I and stellate astrocytes in layers II and VI were labeled. Labeled cells were also present adjacent to blood vessels in the gyral white matter and in underlying white matter generally. In the hippocampus, labeled cells were present in the polymorphic layer of the dentate gyrus. In the prefrontal cortex, schizophrenia and major depression were characterized by decreased labeling of astrocytes adjacent to blood vessels. There were no significant differences between the diagnostic groups in the other prefrontal layers or in the hippocampus. These results suggest that reduced numbers or functional regulation of pGFAP containing astrocytes occurs in schizophrenia and major depression. The mechanism by which this deficit occurs is not known, but it may adversely effect the regulation of neuronal metabolism, communication, and response to injury.

Adult↗
PubMed2001

The schizophrenia-rheumatoid arthritis connection: infectious, immune, or both?

Schizophrenia and rheumatoid arthritis share an impressive number of similarities. Both are chronic, relapsing diseases of unknown etiology. Both became prominent in the early 19th century and have prevalences of approximately 1% in North America and Europe. Both run in families, have pairwise concordance rates of approximately 30% among monozygotic twins, and are more common among individuals born in urban areas. For both diseases, studies have reported greater exposure to cats in childhood than in controls. Both diseases have been associated with similar class II HLA antigens. Both have also been suspected of having infectious etiology, with similar agents--retroviruses, herpesviruses including EBV, and Toxoplasma gondii--having been associated in some cases. Since there is also a well-documented inverse correlation between these two diseases, it is possible that they share a common infectious and/or immune etiology and that once a person gets one of the diseases then they are relatively immune to the other.

Arthritis, Rheumatoid↗
PubMed2001

Emerging technologies for large-scale screening of human tissues and fluids in the study of severe psychiatric disease.

Neuropsychiatric diseases such as schizophrenia and bipolar disorder are major causes of morbidity throughout the world. Despite extensive searches, no single gene, RNA transcript, or protein has been found which can, on its own, account for these disorders. Recently, the availability of genomic tools such as cDNA microarrays, serial analysis of gene expression (SAGE) and large-scale sequencing of cDNA libraries has allowed researchers to assay biological samples for a large number of RNA transcripts. Similarly, proteomic tools allow for the quantitation of a large number of peptides and proteins. These methods include two-dimensional electrophoresis and surface-enhanced laser desorption/ionization (SELDI). We have initiated experiments which apply these techniques to the comparison of RNAs and proteins expressed in clinical samples obtained from individuals with psychiatric diseases and controls. These methods have the potential to identify pathways that are involved in the pathogenesis of complex psychiatric disorders. The characterization of these pathways may allow for the development of new methods for the diagnosis and treatment of schizophrenia, bipolar disorder, and other human psychiatric diseases.

Electrophoresis, Gel, Two-Dimensional↗
PubMed2001

Serial analysis of gene expression in the frontal cortex of patients with bipolar disorder.

BACKGROUND: Bipolar disorder is a serious brain disease affecting more than a million individuals living in the USA. Epidemiological studies indicate a role for both genetic and environmental factors in the pathogenesis of this disorder. AIM: To identify RNA transcripts that are up- or down-regulated in the frontal cortex regions of individuals with bipolar disorder. METHOD: Serial analysis of gene expression (SAGE) and reverse transcriptase-polymerase chain reaction were used to identify RNA transcripts which are differentially expressed in the frontal cortex of brains obtained postmortem from individuals with bipolar disorder compared with other psychiatric and control conditions. RESULTS: Levels of RNA transcripts encoding the serotonin transporter protein and components of the NF-kappa B transcription factor complex are significantly increased in individuals with bipolar disorder compared with unaffected controls. Increased levels of expression of these RNA transcripts were also detected in the brains of some individuals with schizophrenia and unipolar depression. CONCLUSION: The SAGE technique offers promise for the characterisation of complex human brain diseases.

Bipolar Disorder↗
PubMed2000

The antecedents of psychoses: a case-control study of selected risk factors.

Winter birth, urban birth and/or childhood residence, and perinatal complications have each been identified as environmental risk factors for the later development of schizophrenia, schizoaffective disorder, and bipolar disorder. A preliminary case-control study also identified cat exposure in childhood as a possible risk factor. To assess selected environmental events, including childhood exposure to pets, as possible risk factors for these diseases, a case-control telephone survey was carried out by the University of Maryland Survey Research Center for 264 mothers of cases and 528 mothers of matched controls. The cases were randomly selected mothers who were members of the National Alliance for the Mentally Ill, and whose children had been diagnosed with schizophrenia, schizoaffective disorder, or bipolar disorder. The controls were mothers randomly selected from the same telephone exchanges. For five of the 19 major variables, there were statistically significant differences between cases and controls: fever during pregnancy, complications during delivery, city or suburban residence at birth, cat ownership between birth and age 13, and breast-feeding. In a multivariate logistic regression including these five variables, each variable made a significant contribution. The finding of perinatal complications, urban/suburban residence at birth, and cat ownership in childhood as risk factors for the later development of psychoses confirmed previous studies. Previous research on breast-feeding as a risk factor has yielded contradictory results. Additional research is needed to ascertain how such environmental risk factors interact with genetic risk factors. Understanding these could lead to better treatments and possible prevention strategies.

Adolescent↗
PubMed2000

The stanley foundation brain collection and neuropathology consortium.

The Stanley Foundation brain collection is an attempt to supplement existing brain collections for the purpose of promoting research on schizophrenia and bipolar disorder. Specimens are collected with the permission of the families in a standardized manner, with half of each specimen being frozen and half fixed in formalin. The Neuropathology Consortium is a subset of 60 specimens from the collection, well-matched groups of 15 each with diagnoses of schizophrenia, bipolar disorder, major depressive disorder without psychotic features, and normal controls. More than 75000 sections and blocks from the Consortium have been sent to over 50 research groups worldwide to carry out a wide variety of assessments. These data will be integrated to provide a more complete picture of the neuropathology of these disorders.

Adult↗
PubMed2000

Familial and genetic mechanisms in schizophrenia.

A distinction should be made between genetic aspects of schizophrenia and familial aspects. Genetic aspects of the disease have been reviewed and found to be deficient in many respects. Until recent years, familial factors were assumed to be psychological in origin, but this assumption is now discredited. Research efforts should focus on familial factors that are biological, especially infectious agents that may be transmitted within the family. Most infectious agents are influenced by predisposing genes. The etiology of schizophrenia, then, may turn out to involve biological familial infectious agents that are influenced by susceptibility genes governing the infectious process and the clinical expression of the disease.

Animals↗
PubMed2000

Endogenous retroviruses and schizophrenia.

Retroviruses are biologically complex infectious agents which are capable of cellular infection and subsequent integration into the host genome. Retroviruses can exist in an endogenous form in which viral sequences are integrated into the human germline and are vertically transmitted in a Mendelian fashion. The transcriptional activation of these viral sequences in cells within the central nervous system can affect the transcriptional regulation of adjacent genes and result in alterations of neural functioning. This report discusses evidence for a possible role of endogenous retroviruses in the etiopathogenesis of schizophrenia and other human brain diseases. Evidence of endogenous retrovirus activity is manifested by the identification of viral sequences in the brains and cerebrospinal fluids of affected individuals. In addition, affected individuals display evidence of increased activity of virally-encoded reverse transcriptase. The identification of a retroviral component of schizophrenia would be consistent with genetic, environmental, and neurodevelopmental aspects of the disease process. The delineation of a role for retroviruses in disease pathogenesis might lead to new methods for the diagnosis and treatment of schizophrenia.

Animals↗
PubMed2000

Disease-specific alterations in frontal cortex brain proteins in schizophrenia, bipolar disorder, and major depressive disorder. The Stanley Neuropathology Consortium.

Severe psychiatric disorders such as schizophrenia, bipolar disorder and major depressive disorder are brain diseases of unknown origin. No biological marker has been documented at the pathological, cellular, or molecular level, suggesting that a number of complex but subtle changes underlie these illnesses. We have used proteomic technology to survey postmortem tissue to identify changes linked to the various diseases. Proteomics uses two-dimensional gel electrophoresis and mass spectrometric sequencing of proteins to allow the comparison of subsets of expressed proteins among a large number of samples. This form of analysis was combined with a multivariate statistical model to study changes in protein levels in 89 frontal cortices obtained postmortem from individuals with schizophrenia, bipolar disorder, major depressive disorder, and non-psychiatric controls. We identified eight protein species that display disease-specific alterations in level in the frontal cortex. Six show decreases compared with the non-psychiatric controls for one or more diseases. Four of these are forms of glial fibrillary acidic protein (GFAP), one is dihydropyrimidinase-related protein 2, and the sixth is ubiquinone cytochrome c reductase core protein 1. Two spots, carbonic anhydrase 1 and fructose biphosphate aldolase C, show increase in one or more diseases compared to controls. Proteomic analysis may identify novel pathogenic mechanisms of human neuropsychiatric diseases.

Amino Acid Sequence↗