Investigating TDP-43 as neuromarker of Bipolar Disorder

• Grant number: 17/07089-8
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: March 01, 2018
• End date: December 27, 2020
• Field of knowledge: Health Sciences - Medicine - Psychiatry
• Principal Investigator: Beny Lafer
• Grantee: Camila Nascimento Mantelli
• Host Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated scholarship(s): 18/11963-8 - Single-cell sequencing for the study of epigenetic changes in suicide completers with history of child abuse, BE.EP.PD

Abstract

Bipolar disorder (BD) is a chronic and disabling illness that affects 1% to 2,4% of the world population. It is characterized by the recurrence of mania and depression episodes, and the recurrent episodes cause functional impairments, increase in mortality and decline quality of life. The worsening in functioning is also associated to the impact of mood episodes on brain function. Cognitive deficits have also been detected, especially in advanced stages of the disease. This neuroprogressive nature of BD, including essentially psychiatric alterations in the initial stages of the disease that may culminate in cognitive decline at advanced stages, presents similarities with frontotemporal dementia (FTD). This similarity between BD and FTD raises the question of whether these diseases could also be sharing common biological substrates. Transactive response DNA-binding 43 protein (TDP-43) is the main neuropathological marker of FTD. Additionally, the progressive nature of BD along the multiple mood episodes causes brain alterations leading to cellular stress conditions, including oxidative stress and recent evidences demonstrated that TDP-43 plays a role in this process in neural cells. In this context, we aim to study whether TDP-43 could be a neuromarker of BD, which has never been previously investigated. To fill this gap, we will evaluate TDP-43 neuropathological alterations, as well as its protein levels in post-mortem brain tissue from subjects with BD. Samples will be obtained from the Brain Bank of the Brazilian Aging Brain Study Group (BBBABSG). Diagnosis of BD will be made according to the Diagnostic and Statistical Manual IV (DSM-IV), through an interview conducted with an informant close to the deceased subject and able to lend consistent informations. Neuropathological alterations will be analyzed after immunohistochemistry, while TDP-43 levels will be measured using the ELISA-SANDWICH method (LSBio). Once we verify between-group differences (BD vs controls), we intend to select biological pathways that can be associated to TDP-43 function in BD through transcriptome analysis. Therefore, we will use the RNA microarray SurePrint G3 Human Gene Expression Microarrays (Agilent Technologies Santa Clara, CA, United States), which comprises the most recently annotated transcripts.

Scientific publications

(18)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

TATIANA COHAB KHAFIF; ANA KLEINMAN; CRISTIANA CASTANHO DE ALMEIDA ROCCA; GABRIEL OKAWA BELIZÁRIO; EDMIR NADER; SHEILA C. CAETANO; BENY LAFER. Self-regulation in youth with bipolar disorder. Revista Brasileira de Psiquiatria, v. 45, n. 1, p. 20-27, 2023-03-06. (17/07089-8)

ROTENBERG, LUISA DE SIQUEIRA; BORGES-JUNIOR, RENATO GOMES; LAFER, BENY; SALVINI, ROGERIO; DIAS, RODRIGO DA SILVA. Exploring machine learning to predict depressive relapses of bipolar disorder patients. Journal of Affective Disorders, v. 295, p. 681-687, DEC 1 2021. (20/05087-0, 18/11963-8, 17/07089-8)

ROTENBERG, LUISA DE SIQUEIRA; KHAFIF, TATIANA COHAB; MISKOWIAK, KAMILLA WOZNICA; LAFER, BENY. Social cognition and bipolar disorder: pending questions and unexplored topics. Revista Brasileira de Psiquiatria, v. 44, n. 6, p. 9-pg., 2022-11-01. (17/07089-8, 18/11963-8, 20/05087-0)

NASCIMENTO, CAMILA; BARBOSA, ANDRE; NUNES, PAULA; SUEMOTO, CLAUDIA; LEITE, RENATA; GRINBERG, LEA; PASQUALUCCI, CARLOS; NITRINI, RICARDO; JACOB-FILHO, WILSON; BRENTANI, HELENA; et al. Disrupted Genes Modules in the Hippocampus of Older Adults With Bipolar Disorder. BIOLOGICAL PSYCHIATRY, v. 87, n. 9, p. 1-pg., 2020-05-01. (17/07089-8)

NASCIMENTO, C.; NUNES VILLELA, P.; KIM, H. KYUNGHEE; DE OLIVEIRA, K.; PARAIZO LEITE, R. E.; FERRETTI-REBUSTINI, R. E. D. L.; GRINBERG, L. T.; SUEMOTO, C. K.; PASQUALUCCI, C. A.; NITRINI, R.; et al. Unrevealing the role of a frontotemporal dementia protein (TDP-43 protein) in bipolar disorder. European Neuropsychopharmacology, v. 29, p. 1-pg., 2019-01-01. (17/07089-8)

DE SIQUEIRA ROTENBERG, LUISA; COHAB KHAFIF, TATIANA; NASCIMENTO, CAMILA; LAFER, BENY. Emotion Regulation and Bipolar Disorder: Strategies during the COVID-19 Pandemic. BIPOLAR DISORDERS, v. 22, n. 8, p. 879-882, DEC 2020. (17/07089-8)

NASCIMENTO, CAMILA; NUNES, PAULA VILLELA; RODRIGUEZ, ROBERTA DIEHL; TAKADA, LEONEL; SUEMOTO, CLAUDIA KIMIE; GRINBERG, LEA TENENHOLZ; NITRINI, RICARDO; LAFER, BENY. A review on shared clinical and molecular mechanisms between bipolar disorder and frontotemporal dementia. PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY, v. 93, p. 269-283, JUL 13 2019. (17/07089-8)

DE SIQUEIRA ROTENBERG, LUISA; NASCIMENTO, CAMILA; COHAB KHAFIF, TATIANA; SILVA DIAS, RODRIGO; LAFER, BENY. Psychological therapies and psychoeducational recommendations for bipolar disorder treatment during COVID-19 pandemic. BIPOLAR DISORDERS, v. 22, n. 6, p. 644-646, SEP 2020. (17/07089-8)

NASCIMENTO, CAMILA; NUNES, PAULA VILLELA; SUEMOTO, CLAUDIA KIMIE; RODRIGUEZ, ROBERTA DIEHL; PARAIZO LEITE, RENATA ELAINE; GRINBERG, LEA TENENHOLZ; PASQUALUCCI, CARLOS AUGUSTO; NITRINI, RICARDO; JACOB-FILHO, WILSON; BRENTANI, HELENA PAULA; et al. Differential levels of inflammatory and neuroendocrine markers in the hippocampus and anterior cingulate cortex of bipolar disorder subjects: A post-mortem study. BRAIN BEHAVIOR AND IMMUNITY, v. 90, p. 286-293, NOV 2020. (17/07089-8, 16/24326-0)

NASCIMENTO, CAMILA; NUNES, V, PAULA; KIM, HELENA K.; LEITE, RENATA E. P.; RODRIGUEZ, ROBERTA D.; DE OLIVEIRA, KATIA CRISTINA; BRENTANI, HELENA P.; JACOB-FILHO, WILSON; NITRINI, RICARDO; PASQUALUCCI, CARLOS A.; et al. Increased levels of TAR DNA-binding protein 43 in the hippocampus of subjects with bipolar disorder: a postmortem study. JOURNAL OF NEURAL TRANSMISSION, v. 129, n. 1, p. 95-103, JAN 2022. (17/07089-8)

SALDANHA, NANCI MOREIRA; SUEMOTO, CLAUDIA KIMIE; RODRIGUEZ, ROBERTA DIEHL; LEITE, RENATA ELAINE PARAIZO; NASCIMENTO, CAMILA; FERRETI-REBUSTINI, RENATA; DA SILVA, MAGNOLIA MOREIRA; PASQUALUCCI, CARLOS AUGUSTO; NITRINI, RICARDO; JACOB-FILHO, WILSON; et al. beta-amyloid pathology is not associated with depression in a large community sample autopsy study. Journal of Affective Disorders, v. 278, p. 372-381, JAN 1 2021. (16/24326-0, 17/07089-8)

NICOLE REZENDE DA COSTA; LIVIA MANCINE; ROGERIO SALVINI; JULIANA DE MELO TEIXEIRA; ROBERTA DIEHL RODRIGUEZ; RENATA ELAINE PARAIZO LEITE; CAMILA NASCIMENTO; CARLOS AUGUSTO PASQUALUCCI; RICARDO NITRINI; WILSON JACOB-FILHO; et al. Microcephaly measurement in adults and its association with clinical variables. Revista de Saúde Pública, v. 56, 2022-05-27. (16/24326-0, 18/16626-0, 17/07089-8)

TATIANA COHAB KHAFIF; ANA KLEINMAN; LUISA DE SIQUEIRA ROTENBERG; BENY LAFER. Emotion regulation and the COVID-19 pandemic: a practical guide to rehabilitating children and adolescents. Revista Brasileira de Psiquiatria, v. 44, n. 3, p. 235-236, 2021-12-06. (18/11963-8, 20/05087-0, 17/07089-8)

SANTOS, PETALA MATUTINO; CAMPOS, GIOVANNA PEREIRA; NASCIMENTO, CAMILA. Endo-Lysosomal and Autophagy Pathway and Ubiquitin-Proteasome System in Mood Disorders: A Review Article. NEUROPSYCHIATRIC DISEASE AND TREATMENT, v. 19, p. 19-pg., 2023-01-01. (17/07089-8)

NUNES, PAULA VILLELA; SUEMOTO, CLAUDIA KIMIE; RODRIGUEZ, ROBERTA DIEHL; LEITE, RENATA ELAINE PARAIZO; NASCIMENTO, CAMILA; PASQUALUCCI, CARLOS AUGUSTO; NITRINI, RICARDO; JACOB-FILHO, WILSON; GRINBERG, LEA T.; LAFER, BENY. Neuropathology of depression in non-demented older adults: A large postmortem study of 741 individuals. NEUROBIOLOGY OF AGING, v. 117, p. 10-pg., 2022-06-13. (16/24326-0, 17/07089-8, 18/16626-0)

KHAFIF, TATIANA COHAB; ROTENBERG, LUISA DE SIQUEIRA; NASCIMENTO, CAMILA; BERALDI, GABRIEL HENRIQUE; BIPOLAR, BENY LAFER. Emotion regulation in pediatric bipolar disorder: A meta-analysis of published studies. Journal of Affective Disorders, v. 285, p. 86-96, APR 15 2021. (17/07089-8)

NASCIMENTO, CAMILA; KIM, HELENA KYUNGHEE; NUNES, PAULA VILLELA; LEITE, RENATA ELAINE PARAISO; CRISTINA, DE OLIVEIRA KATIA; BARBOSA, ANDRE; BERTONHA, FERNANDA BERNARDI; MOREIRA-FILHO, CARLOS ALBERTO; JACOB-FILHO, WILSON; NITRINI, RICARDO; et al. Gene expression alterations in the postmortem hippocampus from older patients with bipolar disorder-A hypothesis generating study. JOURNAL OF PSYCHIATRIC RESEARCH, v. 164, p. 6-pg., 2023-06-30. (17/07089-8)

GABRIEL, FERNANDA C.; OLIVEIRA, MANOELA; BERK, MICHAEL; BRIETZKE, ELISA; JACKA, FELICE N.; LAFER, BENY. Nutrition and bipolar disorder: a systematic review. NUTRITIONAL NEUROSCIENCE, v. N/A, p. 15-pg., 2022-05-24. (20/05087-0, 18/11963-8, 17/07089-8)