Retinal biomarkers in monogenic vascular cognitive impairment and dementia

Project Summary/Abstract The project will enroll 180 persons with the autosomal dominant gene for Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) to investigate retinal imaging measures as potential diagnostic, prognostic, and disease monitoring biomarkers for clinical trial readiness.

CADASIL is a rare disease and the most heritable monogenic form of vascular cognitive impairment and dementia. The research design will allow the examination using the full spectrum of vascular dementia from presymptomatic gene carriers through dementia. This research is novel from any other in its efforts to study a

single-gene vascular dementia group throughout the life span in an effort to reduce vascular dementia heterogeneities selecting persons enriched for certain future vascular disease secondary to NOTCH3 gene mutation. CADASIL has been considered a good single-gene model of small vessel disease and vascular

dementia. By improving our understanding of CADASIL and its progression, we will be better able to understand the more common sporadic vascular dementias. Since many known neurodegenerative diseases are determined at autopsy to be mixed dementias with a vascular component, the findings from the proposed

research may also impact the large cohorts of neurodegeneration in our aging population. We have established an NIH-funded U.S. multi-site longitudinal natural history study of CADASIL (www.cadasil- consortium.org). The proposed grant aims to build on this ongoing CADASIL study by adding multifaceted

retinal imaging to investigate as a biomarker in CADASIL. Studying the retina – a region that shares numerous embryological and anatomical similarities with the brain – will advance our understanding of various pathologies caused by different NOTCH3 pathogenic variants (PVs). The retina's structural and vascular

features can be demonstrated non-invasively with high resolution optical coherence tomography (OCT) and OCT-angiography (OCT-A). In this project, we will focus on three primary retinal assessments: 1) retinal capillary bed pathology using OCT-A with measures of vessel density (VD), foveal avascular zone (FAZ)

area/effective diameter, vessel tortuosity index (VTI); 2) retinal arteriolar changes using spectral domain (SD) OCT with measures of mean wall thickness (MWT) and lumen diameter (LD) of the superior temporal retinal arteriole; and 3) inner plexiform layer (IPL) thickness as a measure of synaptic injury. At the conclusion of this

research, data will be available to determine the strength of each potential measure as a biomarker for clinical trials in neurodegenerative diseases with cerebrovasculopathies. Findings will facilitate determination of the contexts of use for non-invasive, low-cost retinal imaging biomarkers.