Clinical and biomarker studies in Alzheimer's disease and related disorders

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Biomarkers for Alzheimer's Disease (AD) and other neurodegenerative, neurological and psychiatric diseases In collaboration with Dr. Ed Goetzl (Special Volunteer, NIA), we have pioneered a methodology for isolating blood exosomes and enriching them for neuronal origin by immunoprecipitation using neuronal surface marker L1CAM or astrocytic origin by immunoprecipitation using astrocytic surface marker GLAST. To date, we have conducted several case control studies measuring exosomal beta-amyloid, tau, Ser and Tyr phosphorylated IRS-1, synaptic markers, complement and other proteins, in AD and control subjects. We have found highly significant differences that, for some proteins, accurately discriminate between the two groups. In addition, exosomal differences may be present at the preclinical stage and may predict AD. We have expanded the use of exosome biomarkers in other neurological and psychiatric disorders, demonstrating their ability to identify patients in Restless Legs Syndrome, Multiple Sclerosis, and Schizophrenia. Moreover, we have demonstrated the ability of exosome biomarkers to assess target engagement and response to experimental therapeutics in clinical trials involving patients with AD, Parkinson disease (PD), and bipolar disorder. We have published scores of manuscripts on the topic (including at JAMA Neurology, Journal of Alzheimer's disease, Journal of Neurovirology, Brain Injury, Alzheimer's and Dementia, FASEB J, Cells, Neurology, Annals of Neurology, Annals of Clinical and Translational Neurology, Frontiers in Neuroscience, Multiple Sclerosis Journal, and WIRES RNA). We recently showed that exosome biomarkers predict future cognitive decline and future AD diagnosis in large preclinical cohorts from the Baltimore Longitudinal Study on Aging, the Wisconsin Registry for Alzheimer's Prevention, and Atherosclerotic Risk in Communities. In addition, we showed that exosome biomarkers predict treatment response and show target engagement in clinical trials of metabolic interventions in AD (intranasal insulin) and PD (exenatide). One major goal for the coming years is to conduct studies seeking to demonstrate the relationship between exosomal markers and other biomarkers for AD (PET, CSF) in large preclinical/early clinical cohorts.These studies are needed to assess longitudinal changes in exosome markers and their potential to predict AD at the preclinical stage, disease progression and conversion from MCI to AD. We are planning to study a large cohort of participants in the Women's Health Initiative Long Life Study to assess the relationship of exosome biomarkers with cognitive resilience and APOE e4 genotype. In addition we intend to further validate exosome biomarkers against CSF biomarkers, amyloid and tau PET and, potentially, brain pathology leveraging ante-mortem samples and brain autopsy findings, using various cohorts. Finally, we will try to combine exosomal RNA and lipids with protein biomarkers to further improve diagnostic performance. In addition to a main focus on AD, we are conducting exosome biomarker studies in vascular cognitive impairment/vascular dementia, Parkinson's disease (e.g. response to exenatide), Lewy Body disease, Multiple Systems Atrophy, Traumatic Brain Injury, Restless Legs Syndrome (e.g. showing increased exosome ferritin in neuronal exosomes in the disease), Multiple Sclerosis, Schizophrenia, and Bipolar Disorder. In addition, we have employed a novel Magnetic Resonance Spectroscopy (MRS) methodology at the NIA 3T MRI facility, which allows us to obtain in vivo measures on brain metabolites (glucose, lactate, ketone bodies) and neurotransmitters (glutamate and GABA), which are relevant to AD pathogenesis. Previously, we showed higher glucose and lactate, and lower glutamate and GABA in patients compared to controls, suggesting that these MRS markers may be used as diagnostic biomarkers for AD. Glucose concentration is positively correlated with age. Clinical studies in cognitive aging/prevention of cognitive decline I am conducting a study of Intermittent caloric restriction (CR)implementing 5-2 CR (alternating 5 days of regular calorie intake and 2 days of CR). This is a 8-week study of 5-2 CR in overweight middle aged subjects to assess potential beneficial effects on insulin resistance, brain metabolism, cognitive performance, fMRI activity and biomarkers. If this study is positive, 5-2 CR may be a candidate intervention for primary prevention of AD at midlife. Moreover, we have secured funding from the NIH Office of Dietary Supplements and IRB approval to conduct a randomized controlled study of an oral ketone ester in middle aged individuals with metabolic syndrome. Using MRS and exosome biomarkers, we aim to demonstrate an increase in brain ketone concentration and a switch of brain metabolism towards ketone utilization, alongside improvements in cognitive performance. We have formed a collaboration with Investigators at McGill University, Canada, who plan to start a clinical trial of intranasal insulin in the peri-operative period of heart surgery patients to prevent post-operative cognitive decline. Our main goal is to conduct exosome biomarker analysis showing target engagement and pharmacodynamic response to intranasal insulin. The project has received additional funding from the Alzheimer's Drug Discovery Foundation. In collaboration with Dr. Mohamad El Haj from University of Lille, France, I have been involved in the design and analysis of clinical studies on cognitive features of Alzheimer's disease. For instance, we looked at autobiographical generation of past and future events in a cohort of AD patients compared to controls. We found that future and past events are more similar in patients compared to controls and that the ability to generate future events is closely related with the patient's episodic memory. In addition, the ability to generate future events was associated with Frontal Lobe functions. These findings suggest that remembering the past and imagining the future rely on common brain structures, which are both impaired in AD. In addition, we assessed effects of isolation on Alzheimer's patients residing in nursing homes, as a result of COVID-19, and its impact on paid caregivers.