Validating Blood Biomarkers of Brain Immune and Metabolic Dysfunction in Gulf War Illness
Abstract
Now, 30 years after the 1990-1991 Gulf War (GW), 250,000 Veterans of that era still suffer from Gulf War Illness (GWI), a debilitating multisymptom condition that presents with chronic fatigue, widespread pain, and most commonly, cognitive difficulties. To date, this illness remains difficult to diagnose, and many GW Veterans have not yet received an appropriate medical diagnosis of their condition. At present, most diagnostic processes in GWI rely heavily on self-report of symptoms, which indicates a need to identify tools that can provide an objective diagnosis of GWI. Given the ease of access to blood and the minimally invasive nature of blood collection, biological markers (biomarkers) in blood are desirable for routine clinical use. Furthermore, clinical studies have shown that in the brains of Veterans with GWI, there is reduced utilization of certain energy molecules and increases in immune cells that cause the brain to become inflamed (inflammation). These studies provide strong support that dysregulation of energy and inflammation may be a part of the underlying biological features of GWI. As such, it is important that blood biomarker discovery efforts are designed to take these key aspects of GWI into consideration when developing and validating blood biomarkers of GWI. In both mouse models of GWI and Veterans with GWI, we show that energy problems and inflammation are reflected in changes in blood lipids (water insoluble fats that include oils found in our body or are acquired from one’s diet) and their breakdown products (metabolites). The goal of the proposed study is to determine if those changes in lipid profiles present in the blood of Veterans with GWI similarly indicate of ongoing cognitive impairment and energy deficits and inflammation in the brains of Veterans with GWI, particularly in the presence of Apolipoprotein E (APOE), a prominent genetic risk factor for Alzheimer’s disease (AD). Validation of blood biomarkers, such as these altered lipids and metabolites, can provide an insight into the pathobiology of GWI. We anticipate that lipid/metabolite biomarkers could be used for accurate diagnosis of GWI so that clinicians are able to provide appropriate care and management of Veterans suffering from GWI. It is now well known that many pesticides used during the 1991 GW have high affinity for lipids and target brain and adipose tissue that are rich in lipid content. Studies also suggest that after GW pesticide exposure, there are disturbances in the way the body processes, stores, and transports lipids, particularly in certain intracellular compartments that metabolize lipids to generate energy (i.e., peroxisomes and mitochondria). This may result in the accumulation of harmful lipids that promote oxidative stress, which occurs due to an excessive increase in reactive oxygen molecules and a reduction of antioxidants in the body. Buildup and abnormal processing of harmful lipids can trigger oxidative stress followed by inflammation, but harmful lipids can also directly cause inflammation. As previously demonstrated in our mouse studies, disruption of lipid processing and regulation in the brain after exposure to GW pesticides results in accumulation of harmful lipids and chronic damage to the brain. These disturbed lipid profiles are also present in the blood of Veterans with GWI and may provide some information about the underlying disease process in GWI and, as such, potentially serve as biomarkers of this illness. Previous animal studies have shown that after exposure to pesticides similar to GW chemicals, mice that are genetically modified to produce human APOE E4 protein showed greater cognitive decline than mice without the E4 protein. Human carriers of the E4 allele are similarly at an increased risk of developing age-related cognitive decline and subsequently AD. E4 carriers may experience a greater reduction in brain white matter volume and slowing of information processing speed than E4
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110655
Entities
People
- Laila Abdullah
Organizations
- Roskamp Institute
- United States Army