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Human Neuroscience Unit

Dimitrios Kapogiannis, M.D., Unit Head

The Human Neuroscience Unit at the Laboratory of Neurosciences conducts biomarker and clinical interventional studies on aging-associated neurological disorders, with a primary focus on Alzheimer’s disease (AD).

Our first goal is the development of blood-based biomarkers for AD and other neurological disorders from circulating extracellular vesicles (EVs) enriched for neuronal origin. Our Lab has pioneered a new approach to biomarker discovery by deriving neuronal-origin EVs from peripheral blood. Given their origin, neuronal EVs can be used to interrogate brain pathogenic processes previously inaccessible in vivo, akin to a “liquid biopsy”.

Our second goal is the study of brain insulin resistance (IR) and the development of EV and Magnetic Resonance Spectroscopy (MRS) biomarkers reflecting brain metabolism. Ongoing studies demonstrate that EV biomarkers of brain IR can respond to interventions that target brain metabolism raising the possibility of using them for demonstrating target engagement in clinical trials. In addition, we have developed a novel bioinformatics approach linking regional brain gene expression with AD pathology and have implemented it to study how IR-related genes affect regional vulnerability to AD.

Our third goal is to conduct clinical interventional studies targeting brain metabolism and IR (exendin-4, intermittent calorie restriction) to treat or prevent AD. To test the underlying hypotheses in-depth, these studies utilize EV and MRS biomarkers alongside clinical outcomes.

  • EV-based biomarkers for AD and other neurological disorders
  • Interventional studies

Exendin-4 Clinical Trial: Exendin-4 (or exenatide) is an agonist of glucagon-like peptide-1 (GLP-1) receptors that has been shown to engage multiple targets in the pathogenesis of AD. We have recently completed a phase II, double blind, randomized, placebo-controlled, clinical trial to assess the safety and tolerability of exenatide in participants with Mild Cognitive Impairment (MCI)/early AD and generate preliminary efficacy data. We are currently analyzing outcome measures include safety and tolerability, cognitive performance (ADAS-cog), clinical status (CDR sum of boxes), MRI-measured atrophy, default mode network activity (resting state fMRI), MRS-measured metabolites and neurotransmitters, and cerebrospinal fluid and plasma biomarkers, including exosomal biomarkers. Find more details about the Exendin-4 Clinical Trial.

5-2 Calorie Restriction Clinical Trial (ongoing): We have been promoting the view that brain IR is a risk factor for AD and that targeting brain IR in middle age is a viable primary prevention intervention. We are assessing the brain effects of reducing systemic and brain IR through a powerful dietary intervention, 5-2 CR, defined as 2 consecutive days of consuming 500-600 kilocalories followed by non-restricted eating for 5 days. We are conducting a randomized controlled study of 8-weeks of 5-2 CR vs control continuous diet in overweight middle-aged participants with peripheral IR and no clinical cognitive dysfunction. The ratio of pY/pSer312 IRS-1 in L1CAM+ EVs is the primary outcome. In addition, we collect exploratory outcomes on peripheral metabolism, cognitive performance (memory and executive function), fMRI activity and MRS biomarkers. The study is open to recruitment. Find more details about the 502 Calorie Restriction Clinical Trial.