title: Circulating biosignatures of late-life depression (LLD): Towards a comprehensive, data-driven approach to understanding LLD pathophysiology.
abstract: There is scarce information about the pathophysiological processes underlying Late-Life Depression (LLD). We aimed to determine the neurobiological abnormalities related to LLD through a multi-modal biomarker approach combining a large, unbiased peripheral proteomic panel and structural brain imaging. We examined data from 44 LLD and 31 control participants. Plasma proteomic analysis was performed using a multiplex immunoassay. We evaluated the differential protein expression between groups with random intercept models. We carried out enrichment pathway analyses (EPA) to uncover biological pathways and processes related to LLD. Machine learning analysis was applied to the combined dataset to determine the accuracy with which specific proteins could correctly discriminate LLD versus control participants. Sixty-one proteins were differentially expressed in LLD (p < 0.05 and FDR < 0.01). EPA showed that these proteins were related to abnormal immune-inflammatory control, cell survival and proliferation, proteostasis control, lipid metabolism, intracellular signaling. Machine learning analysis showed that a panel of three proteins (C-peptide, FABP-liver, ApoA-IV) discriminated LLD and control participants with 100% accuracy. The plasma proteomic profile in LLD revealed dysregulation in biological processes essential to the maintenance of homeostasis at cellular and systemic levels. These abnormalities increase brain and systemic allostatic load leading to the downstream negative outcomes of LLD, including increased risk of medical comorbidities and dementia. The peripheral biosignature of LLD has predictive power and may suggest novel putative therapeutic targets for prevention, treatment, and neuroprotection in LLD.
authors.affiliation: Department of Psychiatry & Behavioral Sciences, University of Texas Health Science Center at Houston, Houston, TX, USA.
authors.forename: Breno Satler
authors.initials: BS
authors.lastname: Diniz
authors.affiliation: Department of Biostatistics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA.
authors.forename: Chien-Wei
authors.initials: CW
authors.lastname: Lin
authors.affiliation: Campbell Family Mental Health Research Institute of CAMH, Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
authors.forename: Etienne
authors.initials: E
authors.lastname: Sibille
authors.affiliation: Department of Biostatistics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA.
authors.forename: George
authors.initials: G
authors.lastname: Tseng
authors.affiliation: Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Francis
authors.initials: F
authors.lastname: Lotrich
authors.affiliation: Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Aizenstein
authors.affiliation: Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Charles F
authors.initials: CF
authors.lastname: Reynolds
authors.affiliation: Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Electronic address: butterma@upmc.edu.
authors.forename: Meryl A
authors.initials: MA
authors.lastname: Butters
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001054:Apolipoproteins A / Q000097:blood; D015415:Biomarkers / Q000097:blood*; D001798:Blood Proteins / Q000378:metabolism*; D002096:C-Peptide / Q000097:blood; D003863:Depression / Q000097:blood* / Q000503:physiopathology*; D050556:Fatty Acid-Binding Proteins / Q000097:blood; D005260:Female; D006801:Humans; D008297:Male; D040901:Proteomics; D011569:Psychiatric Status Rating Scales
chemical_list: D001054:Apolipoproteins A; D015415:Biomarkers; D001798:Blood Proteins; D002096:C-Peptide; D050556:Fatty Acid-Binding Proteins
keywords: Elderly; Late-life depression; Neurobiology; Proteomic