Fundamentals

Fundamentals

Principal biomarkers related to Neurodegenerative disease

Amyloid beta protein.  Amyloid-β protein (Aβ) plaques are the characteristic AD pathology first identified by Dr. Alzheimer in the brains of deceased demented patients over a century ago.  Alzheimer’s can only be confirmed after death by the significant presence of Aβ plaques in the brain4, but identification of patients on the AD continuum requires in vivo or in vitro biomarkers to detect Aβ either in the brain, cerebral spinal fluid, blood, or other organs that can act as a surrogate for true amyloid positivity.  Cleavage of the amyloid precursor protein (APP) results in production of amyloid peptides with a range of residues from 17 to 43, although the peptides of most interest are Aβ42 and Aβ40.5

Tau protein.  The other hallmark of Alzheimer’s is the presence of tau tangles in the brain.  Tau tangles result from the breakdown of axonal microtubules, releasing tau protein and resulting in axonal death. Hyperphosphorylated tau increases its likelihood to create fibrils, which leads to microtubule destabilization, axon failure, and eventual neuronal failure.6

α-Synuclein. An abundant neuronal protein involved in vesicle fusion and neurotransmitter release. Present as misfolded proteins in Lewy bodies and Lewy neurites characteristic of Parkinson’s disease dementia (PDD) or dementia with Lewy bodies (DLB).7

Neurofilaments.  Essential for axonal growth, structural support and the transmission of electrical impulses.  Increased levels of the light filament variant is seen in various neurodegenerative diseases and brain injuries, correlating with cognitive impairment and neuronal loss.8

Transactive response DNA-binding protein 43 (TDP-43).  TDP-43 contributes to neuroinflammation and may have a role in mitochondrial and neural dysfunction.  It is characteristic of frontotemporal lobar degeneration (FTLD) and sporadic amyotrophic lateral sclerosis (ALS).5

Biological rationale linking Retinal AF to disease

The retina is a part of the central nervous system, originating as an outgrowth of the developing brain and shares many similarities with the brain. The retina is easily accessible for direct and noninvasive imaging with high spatial resolution and sensitivity, providing an ideal diagnostic target.9,10  It has been shown that Aβ plaques occur in the retinas in addition to the brains of Alzheimer’s sufferers, and furthermore exhibit autofluorescence that is easily visible with slightly modified standard ophthalmic equipment.

Aβ appears in the neural retina due to the same processing pathways of amyloid precursor protein (APP) into amyloid beta fragments as occurs in the brain11. In the retina, APP is synthesized by retinal ganglion cells.12,13  In addition to the production of Aβ in place, the connection of the retina and brain via the optic nerve presents the possibility of retrograde (or anterograde) transport of intracellular amyloids and APP.

The presence of amyloid beta in the neural retina of Alzheimer’s patients has been demonstrated by multiple research groups.  In 2011, Koronyo et al. reported that Aβ plaques were present in the retina of subjects who had postmortem confirmation of AD diagnosis using histology. Their work used immunohistochemistry labeling of Aβ in the retina and found plaque concentrations and morphology similar to those in the brain, in stark contrast with the absence of plaques in the retinas and brains of a group of non-AD subjects.

In an independent study of 16 post mortem eyes and brains from 16 donors with neurological disorders, including 13 with AD, Campbell et al. report that amyloid deposits were present in all the AD eyes and neither of the two non-AD eyes.14 Subsequently Campbell et al. reported that retinal amyloid had a 100% sensitivity for AD in a group of matched eyes and brains from 26 donors analyzed post mortem.15  Campbell’s method was analogous to Koronyo et al. in that ex vivo staining of human retinas was conducted on retinal flat mounts and the retinal area surveyed for evidence of Aβ.

In 2017 Koronyo et al. published further work showing the strong correlation between retinal and cerebral plaque load in AD subjects and non-AD matched controls, and the significantly larger retinal amyloid burden in AD subjects versus controls, using post-mortem histology.  In addition, retinal autofluorescent imaging was used for the first time qualitatively and quantitatively to demonstrate with high significance that both autofluorescent spot quantity and spot intensity was greater in AD patients than in younger, healthy controls.16

 

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