Human Neuroscience Section
Dimitrios Kapogiannis, Principal Investigator
Neurodegenerative diseases, such as Alzheimer's disease (AD), are characterized by a long preclinical phase with evolving and progressively irreversible pathology. Therefore, biomarkers are essential for identifying patients early in the course of the disease, when disease-modifying interventions may have the greatest chance of success. In addition, biomarkers have the potential to boost therapeutic discovery for neurodegenerative diseases by enriching the participant population in clinical trials for the presence of pathology, and as surrogate outcomes. The Human Neuroscience Section aims to develop biomarkers for preclinical diagnosis of AD and neurodegenerative diseases, precise patient characterization and demonstration of target engagement in clinical trials.
A limitation of biomarkers measured in the soluble phase of blood is their tenuous link to brain pathology, since they are often produced by multiple tissues and their brain-derived fraction has to cross multiple barriers before reaching the circulation. The Human Neuroscience Section has pioneered a new approach to biomarker discovery in AD that addresses this limitation by harvesting extracellular vesicles (EVs) enriched for neuronal and astrocytic origin from blood. Given their origin, neuronal and astrocytic-enriched EVs can be used to interrogate pathogenic processes previously inaccessible in vivo, akin to a "liquid biopsy". The Human Neuroscience Section has identified candidate EV biomarkers that reflect multiple pathogenic processes involved in AD and other neurodegenerative diseases. We are currently in the process of conducting larger-scale validation studies for lead candidate biomarkers and demonstrate their ability to diagnose AD diagnosis at the clinical and preclinical stages.
Given the pathogenic significance of abnormal brain metabolism and the therapeutic potential of targeting brain insulin resistance in AD, the lab is also interested in the use of Magnetic Resonance Spectroscopy biomarkers reflecting brain energy metabolism in AD. Finally, we are conducting early phase interventional studies targeting brain metabolism to treat or prevent cognitive aging and ameliorate AD pathogenic processes. After a pilot double-blind placebo-controlled randomized clinical trial of the antidiabetic agent exendin-4 in early AD, we are currently conducting a controlled randomized clinical trial of 5-2 calorie restriction and a controlled randomized clinical trial of an oral ketone ester, both in middle aged individuals at risk for cognitive impairment. In these studies we are looking at changes in extracellular vesicle and Magnetic Resonance Spectroscopy biomarkers alongside cognitive outcomes.
- K.I. Avgerinos, L. Ferrucci, and D. Kapogiannis, Effects of monoclonal antibodies against amyloid-beta on clinical and biomarker outcomes and adverse event risks: A systematic review and meta-analysis of phase III RCTs in Alzheimer's disease. Ageing Res Rev 68 (2021) 101339.
- Kapogiannis D, Mustapic M, Shardell MD, Berkowitz ST, Diehl TC, Spangler RD, Tran J, Lazaropoulos MP, Chawla S, Gulyani S, Eitan E, An Y, Huang CW, Oh ES, Lyketsos CG, Resnick SM, Goetzl EJ, Ferrucci L. Association of Extracellular Vesicle Biomarkers With Alzheimer Disease in the Baltimore Longitudinal Study of Aging. JAMA Neurol. 2019.
- Athauda D, Gulyani S, Karnati H, Li Y, Tweedie D, Mustapic M, Chawla S, Chowdhury K, Skene SS, Greig NH, Kapogiannis D, Foltynie T. Utility of Neuronal-Derived Exosomes to Examine Molecular Mechanisms That Affect Motor Function in Patients With Parkinson Disease: A Secondary Analysis of the Exenatide-PD Trial. JAMA Neurol. 2019.
- C.J. Nogueras-Ortiz, V. Mahairaki, F. Delgado-Peraza, D. Das, K. Avgerinos, E. Eren, M. Hentschel, E.J. Goetzl, M.P. Mattson, and D. Kapogiannis, Astrocyte- and Neuron-Derived Extracellular Vesicles from Alzheimer's Disease Patients Effect Complement-Mediated Neurotoxicity. Cells 9 (2020).
- Mustapic M, Eitan E, Werner JK Jr, Berkowitz ST, Lazaropoulos MP, Tran J, Goetzl EJ, Kapogiannis D. Plasma Extracellular Vesicles Enriched for Neuronal Origin: A Potential Window into Brain Pathologic Processes. Front Neurosci. 2017;11:278.
- Mullins R, Reiter D, Kapogiannis D. Magnetic resonance spectroscopy reveals abnormalities of glucose metabolism in the Alzheimer's brain. Ann Clin Transl Neurol. 2018;5(3):262-272.