Dysfunction of brain microvascular and lymphatic vessels in obesity-linked cognitive impairment

Cognitive impairment is a common symptom in aging and associated neurological disorders such as Alzheimer’s disease (AD) and dementia, significantly reducing quality of life and causing a heavy burden on our health care system and society in general. Associations between obesity and impaired cognitive function and risk of dementias have recently been recognized. Obesity in mid-life is a predictor of mild cognitive impairment in old age. However, there is still no non-invasive biomarkers for early diagnosis and treatment evaluation of cognitive impairment, including obesity-linked cognitive impairment. Investigation of the pathophysiological changes in obesity-linked cognitive decline is critical for development of sensitive biomarkers and effective interventions. To this end, magnetic resonance imaging (MRI) as a non-invasive neuroimaging technique is a powerful and versatile tool. Cerebral neurovascular abnormalities have been associated with obesity-linked neurological disorders and may contribute to loss of neurons and memory deficits. We recently developed several new MRI techniques that provide non-invasive approaches to assess neurovascular and lymphatic changes, neuroinflammation and blood brain barrier (BBB) integrity in both human and animal brains. Our preliminary data shows that there is a significant memory deficit in obese SP1 transgenic mice corresponding with abnormal neurovascular and lymphatic changes measured by MRI. Thus, we propose to test the hypothesis that obesity induces neurovascular and lymphatic abnormalities and BBB dysfunction in the brain that may contribute to cognitive impairment and its related pathology. Using newly developed MRI methods, we will determine whether any of these abnormalities may be indicators for obesity-linked cognitive decline using a human synphilin-1 (SP1) obesity mouse model and a high-fat diet-induced obesity mouse model. These MRI measures will be validated with histological methods and will be correlated with pathological and cognitive impairment. Aim 1: We will assess abnormalities of small blood vessels in the brains. Aim 2: We will assess abnormalities in the cerebral perivascular space and lymphatic vessels in the brains. Aim 3. We will assess BBB integrity and neuroinflammation in the brains. Aim 4. We will study interactions among the abnormalities in cerebral blood and lymphatic vessels and BBB dysfunction and identify composite MRI markers for the pathogenic process of obesity-linked cognitive impairment. These studies will reveal obesity-induced neurovascular and BBB alterations in brains that are associated with cognitive impairment corresponding to pathological and behavioral changes. Outcomes of these studies will provide novel insights into the neuropathological changes underlying obesity-linked cognitive impairment, and thus may facilitate development of biomarkers for early diagnosis and intervention evaluation, and potential treatment targets for obesity-linked cognitive impairment and other dementia.