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 which 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).
Gulf War Illness
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).
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 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 non-carriers.
Gulf War Illness
Veterans with GWI show the same changes in brain structure and processing speed, thus suggesting that the brain regions affected in E4 carriers may also be affected in ill GW veterans as well. This prompts the evaluation of E4 carrier status in tandem with determining novel biomarker status and will provide a better understanding of genetic vulnerability in the context of GW pesticide exposure.
There are currently no tools for objective diagnosis of GWI. Validation of blood biomarkers and their association with brain inflammation and energy utilization problems along with an assessment of cognitive decline as outlined in this proposal would aid clinicians in ensuring that GW veterans obtain an accurate diagnosis of their condition. Given the expertise available at the Roskamp Institute and inclusion of highly qualified collaborators, we expect to successfully achieve these objectives, which will help improve the health of veterans with GWI.