Retinal Vasculopathy in Alzheimer’s Disease

Abstract

The retina has been increasingly investigated as a site of Alzheimer’s disease (AD) manifestation for over a decade. Early reports documented degeneration of retinal ganglion cells and their axonal projections. Our group provided the first evidence of the key pathological hallmarks of AD, amyloid β-protein (Aβ) plaques including vascular Aβ deposits, in the retina of AD and mild cognitively impaired (MCI) patients. Subsequent studies validated these findings and further identified electroretinography and vision deficits, retinal (p)tau and inflammation, intracellular Aβ accumulation, and retinal ganglion cell-subtype degeneration surrounding Aβ plaques in these patients. Our data suggest that the brain and retina follow a similar trajectory during AD progression, probably due to their common embryonic origin and anatomical proximity. However, the retina is the only CNS organ feasible for direct, repeated, and non-invasive ophthalmic examination with ultra-high spatial resolution and sensitivity. Neurovascular unit integrity is key to maintaining normal CNS function and cerebral vascular abnormalities are increasingly recognized as early and pivotal factors driving cognitive impairment in AD. Likewise, retinal vascular abnormalities such as changes in vessel density and fractal dimensions, blood flow, foveal avascular zone, curvature tortuosity, and arteriole-to-venule ratio were described in AD patients including early-stage cases. A rapidly growing number of reports have suggested that cerebral and retinal vasculopathy are tightly associated with cognitive deficits in AD patients and animal models. Importantly, we recently identified early and progressive deficiency in retinal vascular platelet-derived growth factor receptor-β (PDGFRβ) expression and pericyte loss that were associated with retinal vascular amyloidosis and cerebral amyloid angiopathy in MCI and AD patients. Other studies utilizing optical coherence tomography (OCT), retinal amyloid-fluorescence imaging and retinal hyperspectral imaging have made significant progress in visualizing and quantifying AD pathology through the retina. With new advances in OCT angiography, OCT leakage, scanning laser microscopy, fluorescein angiography and adaptive optics imaging, future studies focusing on retinal vascular AD pathologies could transform non-invasive pre-clinical AD diagnosis and monitoring.

The Value of Optical Coherence Tomography Angiography (OCT-A) in Neurological Diseases

“…For the OCT-A-based detection of microvascular changes in the AD retina, cerebral amyloid angiopathy (CAA) is of particular interest. CAA has been described in the brain of AD patients and is characterized by the deposition of amyloid in the walls of cerebral arteries, which triggers several ischemia-induced pathogenic molecular pathways, finally leading to hemorrhagic complications [ 8 , 11 ]. CAA has been reported to be present in the retina, yet it is unclear if it occurs to the same extent as in the brain.…”

“…Three recent review articles have summarized OCT-A findings in AD patients [ 11 , 12 , 13 ]. Essentially, OCT-A examinations of AD retinas have shown an enlarged FAZ, a decrease of the vascular density of the superficial and deep vascular plexus in the macular region ( Figure 3 ), and also in the radial peripapillary capillary layer.…”

Label-Free Hyperspectral Imaging and Deep-Learning Prediction of Retinal Amyloid β-Protein and Phosphorylated Tau

“…[1] While currently there is no cure, with early diagnosis, the progression of the disease may be slowed and the patient life style may be changed. [2,3] Although AD has been historically perceived as a brain disorder, recent studies indicate that AD also manifests in the eye with mounting evidence of abnormalities in the retina, a sensory extension of the brain. [4][5][6] Particularly, the hallmark pathological signs of AD, amyloid β-protein (Aβ) and neurofibrillary tangles (NFTs) comprised of hyperphosphorylated (p)Tau protein, which have long been described in the brain, have also been identified in the retina.…”

“…[1] While currently there is no cure, with early diagnosis, the progression of the disease may be slowed and the patient life style may be changed. [2,3]…”

Retinal Venular Tortuosity Jointly with Retinal Amyloid Burden Correlates with Verbal Memory Loss: A Pilot Study

“…Yet, imaging of the skull-shielded brain poses various limitations for widespread screening in the clinical setting. The retina is a central nervous system organ that exhibits Aβ deposition and vascular changes [ 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 ] and is far more accessible for repeated and high-resolution imaging [ 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 ]. Dysfunctional pericytes in the blood-brain barrier (BBB) are significant contributors to the pathogenesis of vascular cognitive impairment, including cerebral small vessel and cerebral large vessel disease, as well as AD [ 28 , 43 ].…”