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Summary of the proposed research to perfect a retinal biomarker for early differentiation of Alzheimer and Parkinson Disease patients.
The retina is a window to the brain. Current clinical imaging evidence shows that both in Alzheimer's Disease (AD) and Parkinson Disease (PD) the retina and the axons connecting it to the brain are involved in the pathology. Direct retinal postmortem histological evidence evidence is strong in PD and weaker in AD. Visual impairment in AD and in PD differ. The cellular and extracellular localization of misfolded proteins are different. While some features of AD and PD are common, such as cognitive impairment, it is unknown what happens in the retina. Are the pathological proteins in the retina in the same neuronal types?
We are seeking to obtain pathological evidence. The aim is to perfect a biomarker in 3 to 4 years for early differentiation of Alzheimer and Parkinson Disease patients. Ultimately other neurodegenerative Diseases (NDD) should benefit from the the non-invasive retinal biomarker.
Introduction.
Alzheimer’s (AD) and Parkinson’s disease (PD), the most common NDDs, make up the leading causes of dementia worldwide. With an increasing aging population, the prevalence of these diseases has increased. In NDD post-mortem brain studies provided much information. Nevertheless early and accurate diagnosis of NDD using recent developments in brain imaging and cerebrospinal fluid (CSF) tests are fraught with difficulties of cost and wide spread availability.
Given its accessibility, the eye can serve as a “window” to the brain to develop clinical NDD biomarkers through investigating structure/activity relationships in the visual processing of the NDD eye. Several decades of clinical and translational research has located cellular and circuit changes in the NDD retina. There are apparently disease specific structural and functional impairments in the NDD eye. These disease specific markers provide potential contrasts to develop disease specific ocular, easily accessible, non-invasive retinal biomarkers in NDD. The plan to develop specific signatures in vivo in each disease is based on specific proteinopathies in the retina. The best described ones are tau pathology and Aß deposition in AD and α-synuclein protein deposition in PD. It is now possible to investigate whether retinal morphological changes specific to AD and specific to PD may be associated with specific retinal visual impairment in each disease. In vivo retinal histological changes in the retina may be quantified using the non-invasive technique of Optical Coherence tomography (OCT).
Summary of the background research in our laboratory over the last 4 years.
(See References.3 pivotal publications are noted. Figures 3 and 4 of paper in Annals of Neurology are particularly illustrative.)
1. We have established that the retina is part and parcel of the neural pathology of PD: we demonstrated in PD
2. Remodeling of the neural retina
3. Remodeling of the foveal capillary network
4. The presence of intracellular pathological Alpha-Synuclein in
a. amacrine like cells on the border of the inner plexiform/inner nuclear layer, in the typical position of dopaminergic amacrine cells
b. smallish retinal ganglion cells
Studies by us and many others have asserted that retinal changes are correlated with motor abnormalities in PD.
Aim
Based on our in vivo and postmortem studies, together with an impressive amount of evidence from other researchers showing Nerve Fiber Layer (NFL) thinning in the Parkinson and AD eye, we aim to perfect a clinical, non-invasive, inexpensive biomarker.
Vistas of the research: the next steps.
1.We establish retinal structure/ visual function correlation in PD and AD. There is a high probability that the contemplated PD and AD biomarkers are specific to differentiate these two most common illnesses which lead to dementia. With evidence from postmortem histology, the visual biomarkers are going to be expressing specific retinal pathologies.
2. We evaluate the effect of therapy on the retinal biomarkers. We have a medium scale study (n=140) in PD showing that neural remodeling in the PD fovea is differentially sensitive to pre- and post-synaptic dopaminergic therapy. There are no postmortem histological studies in either PD or AD for the retinal and visual effects of non-dopaminergic medications.
3. Based on our current knowledge, both AD and PD can be considered within the broad category of retinopathy and optic neuropathy. Increasing affirmation is available regarding a mitochondrial component in PD at the level of intracellular respiratory enzymes. This link will open up exciting science and clinical opportunities for early specific diagnosis and new treatment modalities.
Future considerations
1.The causality of vascular and neuronal remodeling in the PD retina is a very intriguing question. Is it possible that neuronal remodeling is the cause of the capillary remodeling due to some Growth Factor release of decaying neurons? Or the converse. The question is not only neurobiologically intriguing, but also may lead to the development of new therapeutic considerations.
2. Our current studies show the differential effect of pre- and postsynaptic dopaminergic therapy on neuronal remodeling of the retina. Using the biomarker we shall be in good position to evaluate the effectiveness of new therapies. . .
Key personnel
Ivan Bodis-Wollner MD DSc professor, neurologist, neuroscientist
Piotr Kozlowski MD,professor, neuropathologist
Sofya Glazman MD research Coordinator
References
α-synuclein in the inner retina in parkinson disease. Bodis-Wollner I, Kozlowski PB, Glazman S, Miri S. Ann Neurol. 2014 Jun;75(6):964-6. doi: 10.1002/ana.24182. Epub 2014 Jun 13. PMID: 24816946
Application of an OCT data-based mathematical model of the foveal pit in Parkinson disease. Ding Y, Spund B, Glazman S, Shrier EM, Miri S, Selesnick I, Bodis-Wollner I. J Neural Transm (Vienna). 2014 Nov;121(11):1367-76. doi: 10.1007/s00702-014-1214-2. Epub 2014 Apr 20. PMID: 24748549
The avascular zone and neuronal remodeling of the fovea in Parkinson disease. Miri S, Shrier EM, Glazman S, Ding Y, Selesnick I, Kozlowski PB, Bodis-Wollner I. Ann Clin Transl Neurol. 2015 Feb;2(2):196-201. doi: 10.1002/acn3.146. Epub 2015 Jan 8. PMID: 25750923 Free PMC Article
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