As global life expectancy continues to grow, the prevalence of Alzheimer?s disease (AD) is expected to double every 20 years until 2040. The cognitive decline associated with AD has devastating impact on the quality of life and lifespan of affected individuals, and the enormous societal and economic consequences ? currently around $100B per year in the United States alone ? are one of the major challenges of the 21st century. The preventive treatment necessary to mitigate the impact of AD requires early identification of subjects at risk and reliable predictors of disease progression. Developing such early-intervention strategies requires a thorough understanding of the neurobiological basis of AD and its preclinical stages, such as mild cognitive impairment (MCI). Basic and clinical research has established key pathophysiological processes in MCI/AD development, including deposition of amyloid-b and tau proteins, mitochondrial dysfunction, oxidative stress, and disturbed neurotransmission. Few studies have elucidated the interactions between these processes, and their interactions and relationships ultimately leading to cognitive decline remain poorly understood. Recent advances in edited magnetic resonance spectroscopy (MRS) techniques have opened a new avenue to study the roles of multiple low-concentration brain metabolites in vivo with greatly reduced examination times. It is now possible to simultaneously determine levels of neurotransmitters and neuromodulators (GABA, glutamate, N-acetylaspartylglutamate, aspartate), redox compounds (glutathione, ascorbate), and indicators of mitochondrial dysfunction (lactate) and neuronal integrity (N-acetylaspartate). The initial goal of this proposal is to extend the spatial coverage of these multi-metabolite methods, which are currently restricted to single-voxel measurements, by advancing them into multi-voxel and spectroscopic imaging (MRSI) techniques. In an unprecedented multimodal approach, these methods will be applied in patients with amnestic multi-domain mild cognitive impairment (aMCI-MD, a MCI subtype with particularly high conversion rates to AD), who have previously undergone positron emission tomography (PET) imaging of amyloid-b and tau deposition. Combining the extensive neurometabolic profile with protein mapping will allow to test hypotheses of interactions between amyloid-b and tau deposition, levels of neurotransmitters, antioxidants, and metabolic markers in multiple affected brain regions, and indicators of memory and executive functioning. This Pathway to Independence award will be supported by excellent career development resources at Johns Hopkins University, and training from a mentoring team of globally recognized experts in the fields of MRSI, MRS, molecular imaging and clinical MCI/AD research. It will generate novel tools to study metabolic processes in neurological and neuropsychiatric disorders, and leverage their potential to advance the understanding of MCI/AD neurobiology, potentially indicating new routes toward prediction and prevention.
The prevalence of Alzheimer?s disease is projected to quadruple by 2050 due to the world?s aging population, potentially leading to social and economic crisis. The proposed research project will develop novel magnetic resonance spectroscopic methods to determine a profile of neurometabolic alterations in the brains of patients in early disease stages. These advancements will enhance our understanding of the neurobiological processes leading to cognitive decline, may improve strategies for early identification of individuals at risk of disease progression, and could identify potential approaches for prevention and treatment for this devastating dementia.
