Corneal Confocal Microscopy: A rapid diagnostic and prognostic imaging biomarker for neurodegeneration in dementia

Dementia is a progressive neurodegenerative disease, which causes cognitive and functional impairment and is the 5th leading cause of death globally. Bill Gates and the Alzheimer’s Drug Discovery Foundation (ADDF) have committed $30 million to the diagnostic accelerator programme. It has stated that ‘reliable, affordable, and accessible biomarkers have the potential to revolutionize how we approach Alzheimer's disease (AD) by allowing us to better understand how the disease progresses, more easily identify people for clinical trials, and more accurately monitor their response to treatments’. Similarly, the National Institute of Aging and the Alzheimer's Association (NIA‐AA) have emphasized the need for biomarkers of neurodegeneration to identify those at greatest risk for cognitive decline or progression from mild cognitive impairment (MCI) to dementia. We have pioneered the rapid, non-invasive imaging technique of corneal confocal microscopy (CCM) and we believe this could become a viable biomarker of neurodegeneration in MCI and dementia. Phase 1 is an on-going cross-sectional study where we have established that: • CCM has excellent diagnostic validity for dementia and MCI. • CCM is associated with cognitive and functional decline. Indeed, our preliminary data included in this proposal show that CCM measures have a better diagnostic accuracy (AUC: 70%-80%) to distinguish MCI from normal cognition compared to quantitative measures of brain atrophy (AUC: 60%-70%). Phase 2 (current proposal) will establish the clinical and predictive validity of CCM by increasing the baseline cohort from 210 to 400 participants with MCI and dementia with and without diabetes and include follow-up visits at years 2 and 4. We will also include more detailed neuropsychological testing, blood-based profiling for biomarkers of neurodegeneration, brain volumetric changes and imaging markers of small vessel disease (SVD) to identify individuals with MCI who are at greatest risk of converting to dementia. This project represents a strong clinical and translational research platform involving cross-disciplinary collaboration between 4 centers in Qatar: Weill Cornell Medicine in Qatar (WCM-Q) led by Prof. Rayaz Malik (Lead-PI); the Geriatrics and Memory clinic in Rumailah Hospital led by Dr. Hanadi Alhamad (Co-PI), Interim Translational Research Institute (iTRI), Dr Aiyaz Parray, HMC, Qatar Biomedical Research Institute (QBRI) led by Prof. Omar El-Agnaf (Co-PI). The team at WCM-Q led by Prof. Malik has pioneered CCM as a non-invasive ophthalmic imaging technique to identify neurodegeneration and repair in a range of peripheral neuropathies and central neurodegenerative disorders. Based on data generated in phase 1 we have recently established the diagnostic validity of CCM in a cohort of 56 patients with MCI and dementia without diabetes (Ponirakis et al Annals of Clinical and Translational Neurology https://doi.org/10.1002/acn3.746). The team at QBRI led by Prof. El-Agnaf has an international reputation for the development of highly specific antibodies and the development of specific-ELISA protocols for detecting the pathogenic oligomeric amyloid species associated with neurodegenerative diseases. Dr. Hanadi Alhamad’s team received a 2017 Stars of Excellence award from HMC for achievements in research and health care improvement for phase 1 of this project. This proposal will provide clinical validation of CCM as a biomarker for neurodegeneration in MCI and dementia. This is based on ~20 years of work which has already established analytical and clinical validation of CCM in a range of peripheral and central neurodegenerative disorders including diabetic neuropathy, HIV neuropathy, Parkinson's disease, multiple sclerosis and stroke.

Weill Cornell Medical College in Qatar