Ian PersaudMentor: Dr. Joshua ChiappelliMPRC Conte Research SymposiumAugust 5, 2016

Relationship of Cortisol to Brain

Morphological Abnormalities in

Schizophrenia

SZ and Brain Morphology In a study of 2028 patients and 2540 controls

volume decreases reported in: Hippocampus Amygdala Thalamus Accumbens Intracranial Volumes

Volume increases reported in Pallidum Lateral ventricles

(Van Erp, 2016)

Potential Biomarker?

IN a study of 596 individuals that compared SZ, SAD, BDP, 1° relatives and healthy controls Hippocampal volume supported as putative

biomarker for SZ (P = .007 - .02) and SAD (P = .003 - .14)

(Arnold S 2015)

Diathesis-Stress Model

Stess -events or experiences that jeopardize homeostasis (Chrousos & Gold 1992; Sapolsky, 1992)

Onset, exacerbation, and relapse ALL linked to multiple somatic/environmental stressors

Biological Mechanisms

KYN/A

Methods 91 Hi-res 3T structural MRI scans

48 healthy control, 43 SZ patients Controlled for age and sex

Whole blood samples collected Assays for cytokines, KYNA, and Cortisol

So far, only Cortisol is complete

Manual Hippocampal Volume measurements using Mango 4.0 software

Results No between group hippocampal volume differences

No correlation with cortisol

Significant decrease trend of vol. with age Trend more prominent in patient group

Hippocampal Volume and Age

Overall: (r=-.219, p=.037)Patients: (r=-.397, p=.008, n=43)Controls: (r=-.062, p=.67, n=48)

Accelerated Aging theory Patients with SZ have a faster rate of neural aging,

related to decay. Increased oxidative stress & inflammation

positive feedback mechanisms

Evidence supports Increased oxidative stress biomarkers (Okusaga O. O.

2014) Increased inflammatory biomarkers (Kirpatrick B. & Miller

B.J. 2013)

Allostatic Load Study “The term ‘allostasis’ refers to how an

organism accommodates to a stressor by adjusting homeostatic set points to maintain internal stability” (Nugent et al 2015)

Allostatic Load - 13 biomarkers vs. Cortical thickness

44 Schizophrenia Spectrum Disorder patients, 33 normal controls

Found patients had higher allostatic load, and lower cortical thickness (p=.008)

Hippocampal Volume and Urinary Cortisol

Spearman's rho=-.291, p=.033

Average Cortical Thickness and Plasma Cortisol

Overall: (r=-.198, p=.037)Patients: (r=-.276, p=.043)Controls: (r=-.152, p=.26)

Average Cortical Thickness and C-Reactive Protein

(rho=-.361, p=.005)

Plasma Cortisol and CRP Significant correlation in patients (rho=.429,

p=.013, n=33) but not in controls (rho=-.055,p=.81, n=21)

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Moving Forward Move Forward with KYNA and Cytokine assays to

better explore relationships between these two circuits and neurodegeneration

Understanding the relationship these neurochemicals have with Hippocampal volume, and with patient vs control groups could offer insight to the interaction in the Diathesis-Stress model

Works CitedArnold, S. J. M., Ivleva, E. I., Gopal, T. A., Reddy, A. P., Jeon-Slaughter, H., Sacco, C. B., … Tamminga, C. A. (2015). Hippocampal volume is reduced in schizophrenia and schizoaffective disorder but not in psychotic bipolar i disorder demonstrated by both manual tracing and automated parcellation (FreeSurfer). Schizophrenia Bulletin, 41(1), 233–249. http://doi.org/10.1093/schbul/sbu009

Kirkpatrick, B., & Miller, B. J. (2013). Inflammation and schizophrenia. Schizophrenia Bulletin, 39(6), 1174–1179. http://doi.org/10.1093/schbul/sbt141

Nugent, K. L., Chiappelli, J., Rowland, L. M., & Hong, L. E. (2015). Cumulative stress pathophysiology in schizophrenia as indexed by allostatic load. Psychoneuroendocrinology, 60, 120–129. http://doi.org/10.1016/j.psyneuen.2015.06.009

Okusaga, O. O. (2014). Accelerated aging in schizophrenia patients: the potential role of oxidative stress. Aging and Disease, 5(4), 256–62. http://doi.org/10.14336/AD.2014.0500256

van Erp, T. G. M., Hibar, D. P., Rasmussen, J. M., Glahn, D. C., Pearlson, G. D., Andreassen, O. a, … Turner, J. a. (2016). Subcortical brain volume abnormalities in 2028 individuals with schizophrenia and 2540 healthy controls via the ENIGMA consortium. Molecular Psychiatry, (October 2014), 1–7. http://doi.org/10.1038/mp.2015.63

Walker, E. F., & Diforio, D. (1997). Schizophrenia: A Neural Diathesis-Stress Model. Psychological Review, 104(4), 667–685. http://doi.org/10.1037/0033-295X.104.4.667

Acknowledgements

Dr. Ana Pocivavsek My mentor, Dr. Chiappelli Dr. Elliot Hong Neuroimaging staff, all of the Conte Staff

THANK YOU ALL!