Potential Biomarkers of First-onset Schizophrenia Found in Cerebrospinal Fluid
27 November 2006. One of several holy grails of schizophrenia research is biological markers that could help distinguish schizophrenia from other psychotic disorders, tease out possible subtypes, help predict who might be at risk for developing the disorder, and guide drug development. A team led by Sabine Bahn of the University of Cambridge in the United Kingdom reports in the November PLoS Medicine that they have identified potential biomarkers of schizophrenia in the cerebrospinal fluid of never-medicated, first-episode patients: an upregulation of a peptide from the protein VGF and a downregulation of peptides from the protein transthyretin. They also report a surprising 95 percent sensitivity in distinguishing schizophrenia samples from controls, along with specificity nearly as high.
Screening for biological markers of disease
Biomarkers, such as high blood levels of LDL cholesterol in cardiovascular disease or high blood glucose levels in diabetes, are indicators of a disease state or an increased risk for disease. Even though they may not play a causative role, these molecules are usually linked to the ongoing pathophysiology and can provide information about the mechanisms of disease.
To identify biomarkers of schizophrenia, first author Jeffrey Huang of Cambridge, with collaborators at the University of Cologne in Germany, the Babraham Institute in Cambridge, U.K. and Ciphergen Biosystems in the U.K. relied on a technique called surface-enhanced laser desorption ionization (SELDI) mass spectrometry. SELDI mass spectrometry uses special surfaces to capture proteins and peptides in samples of body fluid while a time-of-flight mass spectrometer is used to quantitate and measure the molecular weights of these compounds. Hundreds of fluid samples can be run at once.
The range of detection is from peptides of less than 1,000 Da up to proteins of 500 kDa. (For a review of SELDI mass spectrometry and its applications, see Tang et al., 2004.) Huang and colleagues used this technology to analyze cerebrospinal fluid (CSF) samples from 41 first-onset, drug-naïve, paranoid schizophrenia patients and 40 demographically matched healthy volunteers. The researchers controlled for various demographic factors, including drugs of abuse.
VGF more abundant in the CSF of schizophrenics
The authors found that a 3,959-Da peptide was 2.8-fold more abundant in samples from schizophrenia patients than it was in samples from controls (P = 10-8); this peptide was subsequently eluted, sequenced, and matched to amino acids 23–62 of the VGF protein. VGF is a neurosecretory protein that is selectively expressed in neurons in brain, particularly in the hypothalamus, and it appears to regulate metabolism (Hahm et al., 1999) and synaptic plasticity (Alder et al., 2003). (For a review of VGF, see Levi et al., 2004; Salton et al., 2000.)
Of note, the researchers were able to elute and sequence a second peptide fragment from VGF with a molecular weight of 3,690 Da. Unlike the 3,959-Da peptide, the amount of the 3,690-Da peptide did not differ significantly between control samples and samples from schizophrenia patients. Both peptides were exactly homologous, save that three amino acids at the N-terminus were absent from the 3,690-Da peptide. According to the authors, “This
indicates that the 40-amino-acid VGF peptide with the ‘APP’ sequence in the amino terminus may have specific functions and/or may be linked to the pathophysiology of schizophrenia.”
To follow up on their VGF findings, Huang and colleagues examined VGF protein expression in schizophrenic postmortem brain tissue—fresh-frozen prefrontal cortex tissue (Brodmann area 9) from gray matter of eight schizophrenics and eight matched controls. A
Western blot analysis with an antibody that recognized the C-terminal sequences of VGF showed strong expression in half of the schizophrenic patients, while no expression of VGF was detected in control brains.
In thinking about the clinical relevance of the VGF findings, Huang and colleagues point out that knocking out the VGF gene in mice produces a lean, hypermetabolic, hyperactive phenotype, implicating VGF in the regulation of energy balance (Hahm et al., 1999). They suggest that “the observation of an increase of the VGF peptide in CSF from patients with schizophrenia, therefore, may point to a hypometabolic state in the schizophrenia brain.” This may or may not be linked to decreased metabolic activity in the prefrontal cortex, or “hypofrontality,” during cognitive activation in patients with schizophrenia (Volz et al., 1999; Meyer-Lindenberg, et al., 2002).
Transthyretin less abundant in the CSF of schizophrenics
In contrast to the upregulation of VGF, the authors found that three peptides from the protein transthyretin were significantly less abundant in the CSF of schizophrenics. Transthyretin is a thyroid hormone-binding protein that transports thyroxine from the bloodstream to the brain (see Schreiber, 2002). The lower levels of the peptides in schizophrenia could not be explained by demographic variables, according to the authors. A possible effect of cannabis use as detected by urine-positive drug screen was ruled out after a two-way ANOVA analysis found no correlation.
Blood transthyretin, largely derived from the liver, contributes to the supply of brain transthyretin. Huang and colleagues also found a significant decrease in serum transthyretin levels; however, they note that no correlation was detected between absolute levels in CSF and those in serum (in opposition to the results of Reiber, 2001), “suggesting that the liver-derived transthyretin may not contribute to the downregulation in CSF.”
As with VGF, postmortem brain studies supported the SELDI mass spectrometry results. The authors found a 40 percent downregulation of transthyretin levels in postmortem prefrontal cortex from patients with schizophrenia by Western blot.
Citing evidence linking transthyretin to the pathophysiology of schizophrenia and other psychiatric diseases, Huang and colleagues note that the reduced levels of transthyretin in the CSF, serum, and brains of schizophrenia patients suggest a lower level of thyroxine transport. “It is noteworthy that thyroid dysfunction is relatively common in patients with schizophrenia (Morley and Shafer, 1982; Ryan et al., 1994) and indeed with other psychiatric disorders (Kirkegaard and Faber, 1998), possibly genetically linked to the disorders. In addition, in patients with severe forms of both hypo- and hyperthyroidism, psychotic symptoms may occur, and the clinical picture frequently resembles that of schizophrenia (Hall et al., 1986, see ref. below), which may imply that an increase in central nervous system thyroxine function may be linked, the authors write. They also point out that long-term administration of clozapine has been implicated in enhancing central nervous system thyroxine function (Chen and Chen, 2007). (In another recent paper, Wan and colleagues  report alterations similar to those seen by Huang and colleagues, though in a tetramer of transthyretin and in response to treatment with the first-generation antipsychotic chlorpromazine.)
To validate their results, the researchers replicated the SELDI mass spectrometry experiments with a second sample of 17 first-onset, drug-naïve schizophrenia patients and 40 demographically matched healthy volunteers, with similar results. “This suggests that these identified alterations in CSF proteins and peptides are a consistent finding and thus may reflect genuinely the early pathophysiology of schizophrenia.” They report that the sensitivity of the overall profile of peptide changes to distinguish schizophrenia from control samples is 80 percent and 88 percent for the original and replication samples, respectively; the sensitivity was found to be 95 percent in both samples.
Disease specificity of the biomarker panel
Lastly, Huang and colleagues made an effort to demonstrate the disease specificity of the VGF and transthyretin results by testing CSF samples from 16 patients with depression and five patients with obsessive-compulsive disorder (OCD) along with CSF samples from another 40 healthy volunteers. Among patients with depression, the VGF peptide (amino acids 23-62) was upregulated and a peptide from the protein secretogranin II was downregulated compared with controls. No significant difference in transthyretin levels was noted. Among the patients with OCD, no differences were seen compared with controls. Additionally, 10 patients with Alzheimer disease and 10 matched controls were tested, with no significant differences found.
“These results indicate that the VGF peptide alone may not be a specific marker for a given psychiatric disease (possibly due to overlapping disease processes, which are not least implied by the fact that patients with a family history of affective
disorder have an increased risk for developing schizophrenia, and vice versa),” the authors write.
To see if their biomarkers might indicate psychosis, not just schizophrenia, they divided their depression patients into those with (n = 3) and without (n = 13) psychotic symptoms. They found no significant differences in the CSF analysis, possibly suggesting that VGF upregulation plus transthyretin downregulation is a biomarker panel of schizophrenia, not just psychosis. They admitted, however, that the sample size of three patients with psychotic depression is too small for any conclusions to be made with real certainty.—Jillian Lokere.
Huang JT, Leweke FM, Oxley D, Wang L, Harris N, Koethe D, Gerth CW, Nolden BM, Gross S, Schreiber D, Reed B, Bahn S. Disease Biomarkers in Cerebrospinal Fluid of Patients with First-Onset Psychosis. PLoS Med. 2006;3(11) [Epub ahead of print]
Hall RCW, Stickney S, Beresford TP (1986) Endocrine disease and behavior.
Integr Psychiatry 4: 122–135. No abstract available.
Comments on News and Primary Papers
Comment by: Stephen J. Glatt
Submitted 4 December 2006
Posted 4 December 2006
I recommend the Primary Papers
This paper by Huang, Bahn, and colleagues makes for very interesting reading and provides an early glimpse into the future of proteomic studies of schizophrenia and other mental disorders. Although some interesting new leads have been provided regarding particular proteins and peptides, these will need replication, as the authors themselves acknowledge. Thus, we should not get caught up in those details at this time, but rather appreciate this work for its greater contribution, which is in the modern theoretical framework that drives the study.
First and foremost, it is refreshing to see a focus on a syndrome, such as psychosis, rather than traditional focus on DSM-based diagnostic boundaries. This approach is one that our group has also endorsed in recent years in light of overlapping linkage, association, and gene expression data in schizophrenia and bipolar disorder. It just makes sense that biomarkers will work best for symptoms or other lower-level traits or states rather than hierarchical diagnoses with questionable validity. In turn, biomarker work performed in this manner may subsequently inform the derivation of novel, biologically based, valid diagnostic categories.
The use of CSF samples is laudatory, since this provides a good balance between access to the central nervous system and ease of sample collection, whereas other modern biomarker studies of blood or postmortem brain tissue do not allow for such balance. The protein-chip technology itself is also impressive, although as with any cutting-edge technology in its infancy, major improvements in resolution and throughput will be needed to move this technique into the mainstream.
In summary, this manuscript should be read carefully by all those among us who are interested in the frontiers of biomarker research on mental disorders. However, in contrast to the authors' statement that "An
alternative approach to genetic studies is to screen for disease markers (biomarkers)," we might be wise to treat biomarker research as a useful adjunct to—rather than replacement for—analyses of genetic polymorphisms.
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Related Paper: Thyroid hormones and retinoids: A possible link between genes and environment in schizophrenia.Comment by: Alan Mackay-Sim
, John McGrath (SRF Advisor)
Submitted 4 January 2006
Posted 4 January 2006
Goodman has previously outlined the evidence implicating retinoids in the etiology of schizophrenia ( Goodman, 1994; Goodman, 1998), and in the current paper expands the focus to include two other members of the nuclear receptor (NR) superfamily—thyroid hormone and (to a lesser extent) estrogen (Palha and Goodman, 2005). The NR superfamily is a phylogenetically ancient system of ligand-activated transcription factors that contributes to fundamental biological processes in metazoans (i.e., from sponges to humans; Escriva et al., 2004). In humans, the best known NRs include those for steroid hormones (glucocorticoid, sex hormones), the seco-steroid vitamin D, thyroid hormone, and the retinoid (vitamin A) family. Evolution has recycled nuclear receptors many times via gene duplication (Escriva et al., 1997), and as a consequence the NR-related pathways underpin a broad sweep of biological functions.
For those interested in generating hypotheses linking NR-related pathways to schizophrenia, the dense cross-talk between members of the NR family and many biological pathways makes for a very wide creative canvas. However, clues from epidemiology can help prioritize NR-related candidates. Sex differences in schizophrenia suggest a role for estrogen (Hafner, 2003; Riecher-Rossler and Seeman, 2002). In particular, the lower incidence of schizophrenia in women (McGrath et al., 2004), the later age of onset, and the better course of illness (Leung and Chue, 2000) implicate sex hormones in this group of disorders. Vitamin D also draws strength from epidemiology, as low prenatal vitamin D may explain the seasonal birth effect (McGrath, 1999), and could contribute to the increased incidence rates in dark-skinned migrants to cold climates (Cantor-Graae and Selten, 2005).
When it comes to exploring NR-related pathways in neuropsychiatric disorders, the real "heavy lifting" involves the translation of hypotheses into more precise descriptive and experimental studies. Hypotheses need to be sharpened by the data, and refined. For example, are there critical windows during the lifespan when disruption of NR-related pathways influences disease risk (e.g., prenatal, peri-onset, all of life)? If ligand concentration influences disease susceptibility, what is the direction of this change (e.g., high or low thyroid hormone, hypo- or hypervitaminosis A)? With respect to genetic susceptibility, should the researcher look for polymorphisms in (a) genes that influence ligand levels; (b) gene coding for the NR; (c) the NR response elements scattered ubiquitously throughout the genome; (d) the thousands of genes that are functionally activated by the NR ligands; or (e) all of the above?
Despite the broad canvas for hypothesis generation, good progress is being made testing these research questions. Gene linkage studies between candidate NR and disease outcomes are a good place to start; however, such studies do not allow for the rejection of NR hypotheses involving disruption of the ligand during development (e.g., low prenatal vitamin D could influence the offspring’s neurocognitive development regardless of maternal or fetal haplotypes).
Transgenic animal models based on NR-related theories of human brain disorders have been very informative—they can help reverse engineer previously hidden layers of complexity (LaMantia, 1999). Disrupting prenatal NR ligand concentration can also help unravel pathways of interest. For example, following up clues from epidemiology, our group has discovered that low prenatal vitamin D alters brain development in the rat (Feron et al., 2005). Adult rats exposed to developmental vitamin D deficiency have enlarged ventricles (Feron et al., 2005) and a behavioral phenotype of interest to schizophrenia research (Becker and Grecksch, 2006; Burne et al., 2004).
Finally, NR-related theories of schizophrenia need clinically based analytic epidemiology. In individuals with schizophrenia, is there any direct evidence of disruption of these pathways? However, if the exposure of interest is during early development (e.g., low maternal thyroid hormone, altered vitamin D or A), then the research community has to rely on banked biological specimens (maternal sera, dried blood spots, etc.). These are rare resources, and limited sample size can result in inconclusive results (McGrath et al., 2003).
Schizophrenia research needs new ideas. In recent years, NRs have provided fertile ground for hypothesis generation. Now is the time to roll up our collective sleeves and examine these candidates in an efficient, but urgent, fashion.
Becker A, Grecksch G. Pharmacological treatment to augment hole board habituation in prenatal Vitamin D-deficient rats.
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Am J Psychiatry. 2005 Jan;162(1):12-24. Review.
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Essays Biochem. 2004;40:11-26. Review.
Escriva H, Safi R, Hanni C, Langlois MC, Saumitou-Laprade P, Stehelin D, Capron A, Pierce R, Laudet V. Ligand binding was acquired during evolution of nuclear receptors.
Proc Natl Acad Sci U S A. 1997 Jun 24;94(13):6803-8.
Feron F, Burne TH, Brown J, Smith E, McGrath JJ, Mackay-Sim A, Eyles DW. Developmental Vitamin D3 deficiency alters the adult rat brain.
Brain Res Bull. 2005 Mar 15;65(2):141-8.
Goodman AB. Retinoid dysregulation as a cause of schizophrenia.
Am J Psychiatry. 1994 Mar;151(3):452-3. No abstract available.
Goodman AB. Three independent lines of evidence suggest retinoids as causal to schizophrenia.
Proc Natl Acad Sci U S A. 1998 Jun 23;95(13):7240-4. Review.
Hafner H. Gender differences in schizophrenia.
Psychoneuroendocrinology. 2003 Apr;28 Suppl 2:17-54.
LaMantia AS. Forebrain induction, retinoic acid, and vulnerability to schizophrenia: insights from molecular and genetic analysis in developing mice.
Biol Psychiatry. 1999 Jul 1;46(1):19-30. Review.
Leung A, Chue P. Sex differences in schizophrenia, a review of the literature.
Acta Psychiatr Scand Suppl. 2000;401:3-38. Review.
McGrath J. Hypothesis: is low prenatal vitamin D a risk-modifying factor for schizophrenia?
Schizophr Res. 1999 Dec 21;40(3):173-7. Review.
McGrath J, Eyles D, Mowry B, Yolken R, Buka S. Low maternal vitamin D as a risk factor for schizophrenia: a pilot study using banked sera.
Schizophr Res. 2003 Sep 1;63(1-2):73-8.
McGrath J, Saha S, Welham J, El Saadi O, MacCauley C, Chant D. A systematic review of the incidence of schizophrenia: the distribution of rates and the influence of sex, urbanicity, migrant status and methodology.
BMC Med. 2004 Apr 28;2:13. Review.
Palha JA, Goodman AB. Thyroid hormones and retinoids: A possible link between genes and environment in schizophrenia.
Brain Res Brain Res Rev. 2005 Nov 30; [Epub ahead of print]
Riecher-Rossler A, Seeman MV. Oestrogens and schizophrenia--introduction.
Arch Women Ment Health. 2002 Nov;5(3):91-2. No abstract available.
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Related Paper: Thyroid hormones and retinoids: A possible link between genes and environment in schizophrenia.
Comment by: Sarah J. Bailey, Michelle A. Lane
Submitted 12 January 2006
Posted 12 January 2006
This review article builds on previous papers hypothesizing a role for thyroid hormone and retinoids in the development of schizophrenia (Goodman, 1998). Retinoids are vitamin A related compounds that act on cells to alter gene expression. In early development, neuronal systems are particularly susceptible to regulation by retinoids, and a key role in defining cells as nerves, nerve cell growth, and connectivity is well established (Maden, 2002; McCaffery et al., 2003). Similarly, thyroid hormone exerts its effects by regulating gene expression and is essential for the regulation of metabolism, growth, and differentiation of the brain. Given this central role in neuronal development, and the numerous neurodevelopmental phenomena associated with schizophrenia, it is perhaps not surprising that thyroid hormone and retinoid-signaling pathways have emerged as important vulnerability targets in schizophrenia. Evidence is also emerging that retinoid-signaling pathways may be important in the function of adult neurons (Crandall et al., 2004; Lane and Bailey, 2005; O' Reilly et al., 2006).
This new article updates the evidence supporting the hypothesis that key components of thyroid hormone and retinoid-signaling pathways are candidate genes that may be involved in the pathology of schizophrenia. Given the prominent role of retinoids in neuronal development, it is perhaps not surprising that mapping of several human chromosomal regions associated with susceptibility to schizophrenia has shown a high coincidence of genes involved in the retinoid signaling cascade at these loci. Deficits in these signaling pathways could cause severe neurodevelopmental deficits, but could also cause more subtle changes in the expression of genes involved in neurotransmission. Of particular interest are the recent studies on altered gene expression in postmortem brain tissues. Several candidate genes that are thought to contribute to increased vulnerability in schizophrenia show altered expression in such studies. That myelination-related genes are differentially regulated in chronic schizophrenia further supports this process as important in the pathology of schizophrenia. Myelination is the process whereby neurons are enveloped in an insulating sheath that permits rapid and effective neuronal signaling. Failures of myelination can severely impair the function of neurons. It is not clear from such postmortem studies which genes are causally related to schizophrenia or which genes might be reactive changes once the disease is manifest. In addition, the finding that some antipsychotic drugs are themselves capable of regulating retinoid-signaling pathways further complicates the interpretation of gene expression studies (Langlois et al., 2001; Ethier et al., 2004).
An important consideration for this hypothesis is whether thyroid hormone or specific retinoids can actually activate the nuclear receptors proposed by Pahla and Goodman, thereby altering gene expression. Although it is tempting to speculate that retinoids and thyroid hormone modulate the expression of a variety of genes through RXR/THR heterodimers, it is important to note that RXR and THR are nonpermissive partners. Nonpermissive nuclear receptor partners can only be activated by the partner receptor’s ligand. In the case of RXR/THR heterodimers, this means that only thyroid hormone can activate gene transcription. RXR ligands, such as 9-cis-retinoic acid or docosahexaenoic acid, cannot (Shulman and Mangelsdorf, 2005). This is thought to allow the THR component of the RXR/THR heterodimer to prevent RXR signaling enabling precise regulation of thyroid hormone target genes (Shulman and Mangelsdorf, 2005).
In addition to inducing gene transcription via RXR/RXR homodimers, 9-cis-retinoic acid can also serve as a ligand for RAR, which can stimulate gene transcription via nonpermissive RAR/RXR heterodimers. However, in vivo, RAR/RXR-mediated gene transcription is believed to be regulated by all-trans-retinoic acid (Soprano et al., 2004) because 9-cis-retinoic acid has been difficult to detect under normal physiological conditions (Horton and Maden, 1995; Kurlandsky et al., 1995; Ulven et al., 2000; Ulven et al., 2001; Werner and DeLuca, 2001). Rather, docosahexaenoic acid, a fatty acid found in the brain, may be the functional RXR ligand in this tissue (de Urquiza et al., 2000; Lengqvist et al., 2004).
While the interaction between thyroid hormone and retinoid signaling pathways is an attractive hypothesis, further work is still required to identify genes that are causally related to schizophrenia, rather than changes in expression that are an adaptation to the disease or pharmacological intervention. There also needs to be more clarity on whether the author’s proposition that retinoids provide a link between genes and environment comes into play early during development or during adulthood.
Crandall J, Sakai Y, Zhang J, Koul O, Mineur Y, Crusio WE, McCaffery PJ (2004). 13-cis-retinoic acid suppresses hippocampal cell division and hippocampal-dependent learning in mice. Proc Natl Acad Sci U S A 101: 5111-5116. Abstract
de Urquiza AM, Liu S, Sjöberg M, Zetterström RH, Griffiths W, Sjövall J, Perlmann T (2000). Docosahexaenoic acid, a ligand for the retinoid X receptor in mouse brain. Science. 290: 2140-4. Abstract
Ethier I, Beaudry G, St-Hilaire M, Milbrandt J, Rouillard C, Levesque D (2004). The transcription factor NGFI-B (Nur77) and retinoids play a critical role in acute neuroleptic-induced extrapyramidal effect and striatal neuropeptide gene expression. Neuropsychopharmacology 29: 335-46. Abstract
Goodman AB (1998). Three independent lines of evidence suggest retinoids as causal to schizophrenia. Proc Natl Acad Sci U S A 95: 7240-4. Abstract
Horton C, Maden M (1995). Endogenous distribution of retinoids during normal development and teratogenesis in the mouse embryo. Developmental dynamics : an official publication of the American Association of Anatomists. 202: 312-23. Abstract
Kurlandsky SB, Gamble MV, Ramakrishnan R, Blaner WS (1995). Plasma delivery of retinoic acid to tissues in the rat. The Journal of biological chemistry. 270: 17850-7. Abstract
Lane MA, Bailey SJ (2005). Role of retinoid signaling in the adult brain. Progress in Neurobiology 72: 275-293. Abstract
Langlois MC, Beaudry G, Zekki H, Rouillard C, Levesque D (2001). Impact of antipsychotic drug administration on the expression of nuclear receptors in the neocortex and striatum of the rat brain. Neuroscience 106: 117-28. Abstract
Lengqvist J, Mata De Urquiza A, Bergman AC, Willson TM, Sjövall J, Perlmann T, Griffiths WJ (2004). Polyunsaturated fatty acids including docosahexaenoic and arachidonic acid bind to the retinoid X receptor alpha ligand-binding domain. Molecular & cellular proteomics : MCP. 3: 692-703. Abstract
Maden M (2002). Retinoid signaling in the development of the central nervous system. Nat Rev Neurosci 3: 843-53. Abstract
McCaffery PJ, Adams J, Maden M, Rosa-Molinar E (2003). Too much of a good thing: retinoic acid as an endogenous regulator of neural differentiation and exogenous teratogen. Eur J Neurosci 18: 457-72. Abstract
O' Reilly K, Shumake J, Gonzalez-Lima F, Lane M, Bailey S (2006). Chronic Administration of 13-Cis-Retinoic Acid Increases Depression-Related Behavior in Mice.
Neuropsychopharmacology. 2006 Jan 4; [Epub ahead of print]
Shulman AI, Mangelsdorf DJ (2005). Retinoid x receptor heterodimers in the metabolic syndrome. The New England journal of medicine. 353: 604-15. Abstract
Soprano DR, Qin P, Soprano KJ (2004). Retinoic acid receptors and cancers. Annual Review of Nutrition 24: 201-221. Abstract
Ulven SM, Gundersen TE, Sakhi AK, Glover JC, Blomhoff R (2001). Quantitative axial profiles of retinoic acid in the embryonic mouse spinal cord: 9-cis retinoic acid only detected after all-trans-retinoic acid levels are super-elevated experimentally. Developmental dynamics : an official publication of the American Association of Anatomists. 222: 341-53. Abstract
Ulven SM, Gundersen TE, Weedon MS, Landaas VO, Sakhi AK, Fromm SH, Geronimo BA, Moskaug JO, Blomhoff R (2000). Identification of endogenous retinoids, enzymes, binding proteins, and receptors during early postimplantation development in mouse: important role of retinal dehydrogenase type 2 in synthesis of all-trans-retinoic acid. Developmental biology. 220: 379-91. Abstract
Werner EA, DeLuca HF (2001). Metabolism of a physiological amount of all-trans-retinol in the vitamin A-deficient rat. Arch Biochem Biophys 393: 262-70. Abstract
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Related News: News Brief—Metabolites in Blood and Urine: Future Laboratory Test for Schizophrenia?Comment by: Stephen J. Glatt
Submitted 22 November 2011
Posted 23 November 2011
I recommend the Primary Papers
This line of work is immensely important, as the lack of reliable biomarkers presents a major barrier to the receipt of a definitive diagnosis and the initiation of treatment; ultimately, the detection of biomarkers that are present at first episode may also signal biomarkers that may be present in the prodrome and even before symptoms emerge, which might provide a basis for earlier intervention and prevention. As elegantly summarized by Drs. Bahn, Guest, and O'Donovan, these results will need replication in diverse samples before they can be capitalized upon in the form of a clinically useful test; however, it does make sense that a biomarker profile derived from multiple sources (serum and urine) might have better explanatory power than a profile derived from just one source. Similarly, the next frontier in the development of biomarker panels may involve what I've called a polyomic approach, taking into account genetic and functional genomic variation as well as metabolite variability as demonstrated here.
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