Joel E Kleinman

Publications (251) View all

• Source

  Available from: Sami S Zoghbi

  Article: A genetic polymorphism for translocator protein 18 kDa affects both in vitro and in vivo radioligand binding in human brain to this putative biomarker of neuroinflammation.

  William C Kreisl, Kimberly J Jenko, Christina S Hines, Chul Hyoung Lyoo, Winston Corona, Cheryl L Morse, Sami S Zoghbi, Thomas Hyde, Joel E Kleinman, Victor W Pike, Francis J McMahon, Robert B Innis
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  ABSTRACT: Second-generation radioligands for translocator protein (TSPO), an inflammation marker, are confounded by the codominant rs6971 polymorphism that affects binding affinity. The resulting three groups are homozygous for high-affinity state (HH), homozygous for low-affinity state (LL), or heterozygous (HL). We tested if in vitro binding to leukocytes distinguished TSPO genotypes and if genotype could affect clinical studies using the TSPO radioligand [(11)C]PBR28. In vitro binding to leukocytes and [(11)C]PBR28 brain imaging were performed in 27 human subjects with known TSPO genotype. Specific [(3)H]PBR28 binding was measured in prefrontal cortex of 45 schizophrenia patients and 47 controls. Leukocyte binding to PBR28 predicted genotype in all subjects. Brain uptake was ∼40% higher in HH than HL subjects. Specific [(3)H]PBR28 binding in LL controls was negligible, while HH controls had ∼80% higher binding than HL controls. After excluding LL subjects, specific binding was 16% greater in schizophrenia patients than controls. This difference was insignificant by itself (P=0.085), but was significant after correcting for TSPO genotype (P=0.011). Our results show that TSPO genotype influences PBR28 binding in vitro and in vivo. Correcting for this genotype increased statistical power in our postmortem study and is recommended for in vivo positron emission tomography studies.Journal of Cerebral Blood Flow & Metabolism advance online publication, 12 September 2012; doi:10.1038/jcbfm.2012.131.
  Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 09/2012; · 5.46 Impact Factor
• Article: Binding of a tritiated inverse agonist to cannabinoid CB(1) receptors is increased in patients with schizophrenia.

  Kimberly J Jenko, Jussi Hirvonen, Ioline D Henter, Kacey B Anderson, Sami S Zoghbi, Thomas M Hyde, Amy Deep-Soboslay, Robert B Innis, Joel E Kleinman
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  ABSTRACT: This study sought to determine whether cannabinoid-1 (CB(1)) receptor binding was altered in the postmortem dorsolateral prefrontal cortex (DLPFC) of individuals with schizophrenia (schizophrenia; n=47) compared to controls (n=43). The CB(1) receptor inverse agonist radioligand [(3)H]MePPEP was used to measure specific binding to CB(1) receptors. The specific binding of [(3)H]MePPEP to CB(1) receptors was 20% higher in patients with schizophrenia than in controls. Power analyses suggested that 53 subjects per group would be needed to detect a similar difference in vivo with positron emission tomography (PET) and the structurally related inverse agonist radioligand [(18)F]FMPEP-d(2) (80% statistical power, p<0.05).
  Biological Psychiatry 08/2012; 141(2-3):185-8. · 8.28 Impact Factor
• Article: Analysis of copy number variations in brain DNA from patients with schizophrenia and other psychiatric disorders.

  Tianzhang Ye, Barbara K Lipska, Ran Tao, Thomas M Hyde, Liqin Wang, Chao Li, Kwang H Choi, Richard E Straub, Joel E Kleinman, Daniel R Weinberger
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  ABSTRACT: Clinical studies have identified several regions of the genome with copy number variations (CNVs) associated with diverse neurodevelopmental behavioral disorders. We analyzed 1 million (M) single nucleotide polymorphism genotype arrays for evidence of previously reported recurrent CNVs and enriched genome-wide CNV burden in DNA from 600 brains, including 441 individuals with various psychiatric diagnoses. We explored gene expression in the dorsolateral prefrontal cortex in selected cases with CNVs and in other subjects with Illumina BeadArrays (568 subjects in total) and additionally in 66-92 subjects with quantitative real-time polymerase chain reaction. The CNVs in previously reported genomic regions were identified in 4 of 193 patients with the diagnosis of schizophrenia (1q21.1, 11q25, 15q11.2, 22q11), 4 of 238 patients with mood disorders (11q25, 15q11.2, 22q11), and 1 of 10 patients with autism (2p16.3). No evidence of increased genome-wide CNV burden was observed in cases with schizophrenia or mood disorders, although the study is underpowered to observe rare events. Messenger RNA expression patterns suggested incomplete molecular penetrance of observed CNVs. Our data confirm in brain DNA the presence of certain recurrent CNVs in a small percentage of patients with psychiatric diagnoses.
  Biological psychiatry 07/2012; 72(8):651-4. · 8.93 Impact Factor
• Article: Use of postmortem human dura mater and scalp for deriving human fibroblast cultures.

  Lindsay A Bliss, Malik R Sams, Amy Deep-Soboslay, Renee Ren-Patterson, Andrew E Jaffe, Josh G Chenoweth, Amritha Jaishankar, Joel E Kleinman, Thomas M Hyde
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  ABSTRACT: Fibroblasts can be collected from deceased individuals, grown in culture, reprogrammed into induced pluripotent stem cells (iPSCs), and then differentiated into a multitude of cell types, including neurons. Past studies have generated iPSCs from somatic cell biopsies from either animal or human subjects. Previously, fibroblasts have only been successfully cultured from postmortem human skin in two studies. Here we present data on fibroblast cell cultures generated from 146 scalp and/or 53 dura mater samples from 146 postmortem human brain donors. In our overall sample, the odds of successful dural culture was almost two-fold compared with scalp (OR = 1.95, 95% CI: [1.01, 3.9], p = 0.047). Using a paired design within subjects for whom both tissues were available for culture (n = 53), the odds of success for culture in dura was 16-fold as compared to scalp (OR = 16.0, 95% CI: [2.1-120.6], p = 0.0007). Unattended death, tissue donation source, longer postmortem interval (PMI), and higher body mass index (BMI) were associated with unsuccessful culture in scalp (all p<0.05), but not in dura. While scalp cells proliferated more and grew more rapidly than dura cells [F (1, 46) = 12.94, p<0.008], both tissues could be generated and maintained as fibroblast cell lines. Using a random sample of four cases, we found that both postmortem scalp and dura could be successfully reprogrammed into iPSC lines. Our study demonstrates that postmortem dura mater, and to a lesser extent, scalp, are viable sources of living fibroblasts for culture that can be used to generate iPSCs. These tissues may be accessible through existing brain tissue collections, which is critical for studying disorders such as neuropsychiatric diseases.
  PLoS ONE 01/2012; 7(9):e45282. · 4.09 Impact Factor
• Source

  Available from: Carlo Colantuoni

  Article: Temporal dynamics and genetic control of transcription in the human prefrontal cortex.

  Carlo Colantuoni, Barbara K Lipska, Tianzhang Ye, Thomas M Hyde, Ran Tao, Jeffrey T Leek, Elizabeth A Colantuoni, Abdel G Elkahloun, Mary M Herman, Daniel R Weinberger, Joel E Kleinman
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  ABSTRACT: Previous investigations have combined transcriptional and genetic analyses in human cell lines, but few have applied these techniques to human neural tissue. To gain a global molecular perspective on the role of the human genome in cortical development, function and ageing, we explore the temporal dynamics and genetic control of transcription in human prefrontal cortex in an extensive series of post-mortem brains from fetal development through ageing. We discover a wave of gene expression changes occurring during fetal development which are reversed in early postnatal life. One half-century later in life, this pattern of reversals is mirrored in ageing and in neurodegeneration. Although we identify thousands of robust associations of individual genetic polymorphisms with gene expression, we also demonstrate that there is no association between the total extent of genetic differences between subjects and the global similarity of their transcriptional profiles. Hence, the human genome produces a consistent molecular architecture in the prefrontal cortex, despite millions of genetic differences across individuals and races. To enable further discovery, this entire data set is freely available (from Gene Expression Omnibus: accession GSE30272; and dbGaP: accession phs000417.v1.p1) and can also be interrogated via a biologist-friendly stand-alone application (http://www.libd.org/braincloud).
  Nature 10/2011; 478(7370):519-23. · 36.28 Impact Factor