Neuro-Immune Biotypes of Depression: Towards Pathophysiology-Based Diagnosis and Personalized Treatment

Lay Summary

Neuro-immune biotypes of depression: towards pathophysiology-based diagnosis and personalized treatment

Exploring a possible neuroimmune subtype of major depression and how it occurs in the brain

This study may lead to improved treatment for an inflammatory subtype of major depressive disorder (MDD). An estimated 40 percent of people with MDD may have an immune biotype that might respond to anti-inflammatory interventions. Prevalent among MDD’s multiple symptoms are “anhedonia” (the inability to experience pleasure), and high levels of anxiety and stress. Inflammation is emerging as an important MDD risk factor and has been linked to MDD associated with obesity, metabolic syndrome and diabetes, and to subsequent Alzheimer’s risk.

The investigators’ preliminary clinical data indicate that a subset of MDD patients have elevated blood levels of an inflammatory protein (an IL-6 cytokine). These patients also showed difficulties learning from rewarding situations. The researchers’ prior animal model studies show evidence that the inflammatory proteins penetrate the BBB in association with stress.

They hypothesize that MDD patients with high inflammatory cytokine levels will have: 1) greater BBB leakiness; and 2) hyper-connections within the “reward circuit” in the brain that gives rise to anhedonia. These characteristics would define a physiologically defined biotype of MDD.

They will study 60 people: 20 MDD patients who have high blood levels of inflammatory cytokines; 20 MDD patients with low cytokine levels; and 20 healthy volunteers. Using a cutting-edge MRI technique (“advanced dynamic contrast-enhanced MRI”) they will try to detect subtle BBB leakage. The technique uses an MRI tracer called gadolinium that is injected into the blood, and shows sites of BBB leakiness in the brain. While this technique has been used to study stroke and tumors, this will be its first use in depression. Thereafter they will use an innovative fMRI technique (“multi-echo multi-band fMRI”) to measure connectivity of the neural circuit involved in reward and anhedonia, to see if the circuit is excessively active in the high inflammation MDD group.

Abstract

Neuro-immune biotypes of depression: towards pathophysiology-based diagnosis and personalized treatment

The current study aims to conduct a high impact, advanced neuro-immune imaging project designed to
integrate clinical, neuroimaging and immunological assessments in order to ultimately advance therapeutic discovery for a specific neuro-immune biotype of major depressive disorder (MDD). MDD accounts for more disability than any other disease worldwide, yet many patients continue to suffer symptoms as current drug discovery efforts are largely stalled due to lack of clearly defined novel drug targets. Critically, recent preclinical work points toward a key role for stress-sensitive integrity of the blood-brain barrier (BBB) in regulating the influence of peripheral immune mediators on brain circuit function leading to a pro-depressive phenotype. Building on this data, the proposed highly translational study will use advanced neuroimaging techniques to characterize the relationship between peripheral immune profiles, neural circuits, and integrity of the stress-sensitive BBB across MDD patients and healthy non-depressed volunteers. Our mechanistic model posits that depression arises in a subgroup of patients through up-regulation of peripheral immune factors and convergent breakdown of the BBB, possibly through a stress-dependent mechanism. The study Aims and hypotheses are as follows.
Aim 1. To link peripheral immune profiles to symptom-specific neurocircuit perturbations in patients with a high-inflammatory biotype of MDD. In Aim 1, we will characterize the connectivity of the VTA-NAc circuit, and additional key circuits that regulate mood, across three study groups: (1) high-inflammatory MDD (n=20), (2) low-inflammatory MDD (n=20), and (3) non-depressed health control (HC) (n=20), and link these neurocircuit measures to specific profiles of circulating immune factors. Hypothesis 1. MDD patients in the high- inflammatory subgroup have abnormal hyper-connectivity within the reward neurocircuit, comprised of the ventral tegmental area (VTA), nucleus accumbens (NAc), and medial prefrontal cortex (mPFC), circuits that regulate anhedonia.
Aim 2. To characterize the role of blood-brain barrier (BBB) integrity in patients with a high-inflammatory biotype of MDD. In Aim 2, we will characterize BBB integrity across the three study groups from Aim 1: (1) high-inflammatory MDD, (2) low-inflammatory MDD, and (3) HC, and test a mechanistic model whereby peripheral circulating immune factors influence the VTA-NAc and other circuits as a function of BBB integrity in order to cause symptoms of anhedonia and other symptoms of depression in a high-inflammatory MDD subtype of depression.
Hypothesis 2.1. MDD patients in the high- inflammatory subgroup have reduced integrity of the BBB (i.e., greater leakiness), compared to low-inflammatory MDD and HC. Hypothesis 2.2. Reduced BBB integrity in MDD is associated with hyper-connectivity within the reward neurocircuit and anhedonia.