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Alzheimer’s disease and the eye

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Dr Christine Nguyen
BScOptom PhD Melb

Jeremiah Lim
BOptom MPhil Melb  DipOptom (SP)

Dr Zheng He
BMed China PhD Melb

Professor Algis Vingrys
BScOptom PGCertOcTher PhD Melb FARVO FAAO

Dr Bang Bui
BScOptom MOptom PGCertOcTher PhD Melb

The ability to non-invasively visualise neurons and blood vessels is an attribute unique to the eye. This window provides an unparalleled view into general health, as many cardiovascular and brain disorders can have manifestations in the eye.1,2,3 These attributes render the eye and in particular, the neuro-vascular retina an ideal surrogate or ‘biomarker’ for systemic and neural disease.

Optometrists know that using the eye as an indicator of systemic disease is not novel. In current optometric care, assessing the eye for signs of diabetic change is standard practice and can offer perspective of the detection and the progression of the diabetes, as well as the effectiveness of ongoing treatment.

More recently, changes in retinal vessel diameter have been shown to be early predictors of stroke4 and studies are ongoing to make this assessment commonplace among ocular health professionals.

In addition to vascular disease, the eye can also give insight into brain disorders. The eye is an out-pouching of the brain and if parallel changes occur in both of these organs, then the retina may provide a unique way to assess cortical disease.

Retinal imaging may provide a simple and inexpensive alternative to cortical imaging, which is limited by the skull. This barrier prevents simple optical imaging of the brain and necessitates the use of expensive and complex cortical imaging techniques such as PET and MRI.

Need for a biomarker

Alzheimer’s disease is a brain disorder that is in desperate need of a viable biomarker. Alzheimer’s is characterised by a progressive decline in memory and executive functions, and its hallmark is the deposition of cerebral beta-amyloid (Aß) deposits. There remains no effective long-lasting treatment for Alzheimer’s and its annual economic cost globally has been estimated at US$600 billion.5

Australia’s baby-boomer bulge means that in the coming decade, a dramatic shift in the demand for health care will manifest itself—from cardiovascular disease and cancer to neurodegenerative conditions.6

At present, the only definitive diagnosis for Alzheimer’s disease is post-mortem confirmation of plaques in the brain.1 Recent clinical findings suggest that successful treatment needs to start in the prodromal stages of the disease, thus making it imperative to have an early biomarker.

The inability to make definitive early diagnosis and monitor disease progression frustrates the development of a cure for Alzheimer’s disease. Less than one in 10 drugs progresses to market,7 in part due to  the lack of effective biomarkers.7 Recent advances in PET imaging show promise in defining biomarkers for Alzheimer’s disease;8,9,10 however, the technology is expensive and its use in everyday practice is limited. An inexpensive, specific and quantitative ocular biomarker of Alzheimer’s disease would improve the likelihood of finding a cure.

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Figure 1. Retinal vessel analysis when used in conjunction with fundus photography provides further insight into cardiovascular4 and brain health15

Eye as a biomarker for Alzheimer’s

While changes in the brain are well recognised in Alzheimer’s disease, growing  evidence shows that the disease also affects the eye.1 Visual symptoms are frequent early complaints in patients with Alzheimer’s disease, including deficiencies in colour vision, contrast sensitivity and motion perception.11,12 Although the origin of some of these symptoms may occur at the visual cortex, other studies have shown that changes do occur in the retina.

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Figure 2. PET imaging using Pittsburgh Compound-B6 is a specific biomarker of Alzheimer’s disease but is expensive as an everyday screening tool

Multiple studies have indicated that Alzheimer’s patients exhibit thinning of retinal nerve fibre layer and an associated reduction in the electroretinogram.1,13 Alzheimer’s disease patients exhibit cerebral blood flow reduction14 and recent studies indicate that retinal vascular changes can also be seen in Alzheimer’s disease.11,15 The hallmark Aß plaque deposits that occur in the brains of Alzheimer’s patients have also been shown to occur in their retinas. Retinal Aß plaques have been identified in tissue from both human Alzheimer’s patients10,16 and rodent Alzheimer’s models.17 A recent study has imaged retinal Aß plaques in vivo in a rodent model (Figure 1) following injection of a contrast agent, curcumin.10

At the University of Melbourne, our group is investigating vascular, neural and structural developments as ocular signs of Alzheimer’s disease and developing non-invasive techniques to analyse them. It is hoped that these studies will translate to a clinical tool that can identify the presence of Alzheimer’s disease and monitor its progression.

This work is supported by the Melbourne Neuroscience Institute through an MNI fellowship to Dr Christine Nguyen and a Strategic Australian Postgraduate Award (STRAPA) doctoral award to Jeremiah Lim. If successful, future optometrists may be able to screen their patients for Alzheimer’s disease, thus playing a key role in early detection of this devastating illness.

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Figure 3. Plaques (numbered 1 to 4) in Alzheimer’s disease can be viewed in vivo in the retina with (green) curcumin staining in rodent eyes10

 

  1. Frost S, Martins RN, Kanagasingam Y. Ocular biomarkers for early detection of Alzheimer’s disease. J Alzheimers Dis 2010; 22: 1-16.
  2. Patton N, Aslam T, Macgillivray T, Pattie A, Deary IJ, Dhillon B. Retinal vascular image analysis as a potential screening tool for cerebrovascular disease: a rationale based on homology between cerebral and retinal microvasculatures. J Anat 2005; 206: 319-348.
  3. Greenberg BM, Frohman E. Optical coherence tomography as a potential readout in clinical trials. Ther Adv Neurol Disord 2010; 3: 153-160.
  4. Wong TY, Klein R, Couper DJ et al. Retinal microvascular abnormalities and incident stroke: the Atherosclerosis Risk in Communities Study. Lancet 2001; 358: 1134-1140.
  5. Wimo A, Prince M. World Alzheimer Report 2010: The Global Economic Impact of Dementia. Stockholm: Alzheimer’s Disease International 2010: 1-51.
  6. Economics A. Keeping dementia front of mind: incidence and prevalence 2009-2050. Canberra: Alzheimer’s Australia; 2009.
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  10. Koronyo-Hamaoui M, Koronyo Y, Ljubimov AV et al. Identification of amyloid plaques in retinas from Alzheimer’s patients and noninvasive in vivo optical imaging of retinal plaques in a mouse model. Neuroimage 2011; 54 Suppl 1: S204-217.
  11. Berisha F, Feke GT, Trempe CL, McMeel JW, Schepens CL. Retinal abnormalities in early Alzheimer’s disease. Invest Ophthalmol Vis Sci 2007; 48: 2285-2289.
  12. Katz B, Rimmer S. Ophthalmologic manifestations of Alzheimer’s disease. Surv Ophthalmol 1989; 34: 31-43.
  13. Parnell M, Guo L, Abdi M, Cordeiro MF. Ocular manifestations of Alzheimer’s disease in animal models. Int J Alzheimers Dis 2012; 2012: 786494.
  14. Nicolakakis N, Hamel E. Neurovascular function in Alzheimer’s disease patients and experimental models. J Cereb Blood Flow Metab 2011; 31: 1354-1370.
  15. Cheung CY, Ong YT, Ikram MK et al. Microvascular network alterations in the retina of patients with Alzheimer’s disease. Alzheimer’s & Dementia 2014; 10: 135-142.
  16. Emptage L, Kisilak ML, Wilson M, Leonenko Z, Campbell M. Sensitivity and specificity of fluorescence and polarimetry of the retina in Alzheimer’s disease. Invest Ophthalmol Vis Sci ARVO E-Abstract Florida, USA; 2014: Abstract 344: 3360: C0059.
  17. Liu B, Rasool S, Yang Z et al. Amyloid-peptide vaccinations reduce {beta}-amyloid plaques but exacerbate vascular deposition and inflammation in the retina of Alzheimer’s transgenic mice. Am J Pathol 2009; 175: 2099-2110.


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