The Answer to Early Diagnosis & Treatment Monitoring of Alzheimer’s Is in the Eye.

The Answer to Early Diagnosis & Treatment Monitoring of Alzheimer’s Is in the Eye

“The eye is quite literally a ‘real window’ to the rest of the body,” according to Dr. Noel Bairey Merz, director of the Women's Heart Center at Cedars Sinai Heart Institute in Los Angeles.

“Diagnosing illness through the eye is nothing new,” according to Dr. Marco Zarbin, chief of ophthalmology at the University of Medicine and Dentistry, New Jersey.

The retina is actually a piece of the brain that has grown into the eye and processes neural signals when it detects light, say the U Penn researchers.

The eye is part of the

brain.

The Approachable Retina:Unlike higher visual centers, the retina provides an excellent source of material for detailed anatomical, physiological, and pharmacological analyses of the neural mechanisms underlying elementary information processing by the vertebrate brain.

The Eye is Part of theCardiovascular System

“The eyes truly are unique real estate,” says Andrew Iwach, MD, executive director of the Glaucoma Center of San Francisco. “They’re the only place in the body where you can see:

a bare nerve, a bare artery, and a bare veinwithout doing any cutting. And the disease processes we see occurring in the eye are probably occurring in the rest of the body.”

By David Freeman, WebMD Feature.http://www.webmd.com/eye-health/features/what-your-eyes-say-about-your-health

“Perhaps of most importance, privileged sites and tissues create a local microenvironment that is

profoundly immunosuppressive.”

Bruch’s membrane abnormalities:

•Age 19: Bruch’s membrane thickened in 72%

•Age 33: Calcifications in the Bruch’s membrane in 59%

•Age 54: Soft drusen found in 10%

De Jong PT, et. Al. Ophthalmology. 1992 Feb;99(2):278. Erasmus University Rotterdam.

“Accumulating evidence suggests that the molecular, structural and functional properties of BM are dependent on age, genetic constitution,

environmental factors, retinal location, and disease state.”

Prog Retin Eye Res. 2010 Jan;29(1):1-18. The dynamic nature of Bruch's membrane

The Eye Through the Ages….

45 50 55 60 65 70 75 80 85 90 95

0

5

10

15

20

25

perfect geometric progression

actual ARMD data

% of ARMD as a Function of Age – Compared to a Perfect Geometric Progression

Disease doubles every 5 years after age 50

Age

Prevalence %

Incidence of Influenza

National Geographic, May 2013

Measuring Aging to determine “at risk” populations before

disease becomes clinically relevant (and costly)

The Age-Related Eye Disease Study (AREDS) – NIHAssociations between

Mortality and Ocular Disorders

AREDS: Arch. Ophthal Vol. 122, 716-726. May 2004.

•1992-1998 – 11 Clinical Centers – 4757 participants

•Indications: AMD and cataract

•Included “early” drusen or retinal pigment epithelial abnormalities

Median follow-up of 6.5 years11.2% of AREDS participants died

Predominant Cause: Cardiovascular event

[email protected] – All Rights Reserved – For A4M Workshop Attendees Only. Do NOT Copy or Distribute

Diagnose

Treat

Monitor

Confi

denti

alAREDS

#13Associais well studied

and not new (3)

15

AMD41%

Vision36%

Cataract Surgery55%

Nuclear Opacity40%

ZincSupplements

Age-Related Eye Diseases are Deadly

AMD - Over 11% Mortality in 6.5 years

The Answer to Early Diagnosis & Treatment Monitoring of Alzheimer’s Is in the Eye –

The Retina

AMD41%

7yrs

Age-Related Eye Diseases are Deadly

Wet AMD – Cat 4

Macular Degeneration– Fundus Photo

Atheromatous plaque

The Answer to Early Diagnosis & Treatment Monitoring of Alzheimer’s Is in the Eye

Drusen contains amyloid beta (Aβ) peptide, the same substance associated with the senile plaques of

Alzheimer’s disease.

Glaucoma by Optical Coherence Tomography (OCT)

Glaucoma is considered a

disease of increased inter-

ocular pressure, with no cure.

Glaucoma is actually an

inflammatory neuro-

degenerative disorder like

Alzheimer’s disease.

Retinal nerve thinning is

now appreciated to be part

of the glaucoma diagnosis.

Neurodegenerative Diseases by OCT“Compared with healthy age-matched controls, the RNFL

thickness of AD patients were much thinner as determined by OCT.”

“OCT is proven useful for the detection of early stages of AD as it allows for a non-invasive visualization of axons of the

central nervous system (CNS) providing cross-section imaging of the retina.”

“OCT could eventually supplement or even replace MRI for tracking multiple sclerosis (MS) severity and progression.”

Retinal nerve fiber layer structure abnormalities in early Alzheimer's disease: Evidence in optical coherence

tomography

Neuroscience Letters Volume 480, Issue 1, 9 August 2010, Pages 69–72

The changes of retinal nerve fiber layer thickness against eye quadrant assessed with optical coherence tomography in two eyes of a control subject (A) and two eyes of a patient with Alzheimer’s disease (B). The chart in the left panel is quantitative data curve while the images in the right panel are raw data.

The eye is part of the brain in health and disease

The Answer to Early Diagnosis & Treatment Monitoring of Alzheimer’s Is in the Eye –

The Lens

27

Measuring Alzheimer’s andCardiovascular Disease in the Lens

Nuclear Cataract

Corneal Stem CellsAlexander Schermer. The Journal of Cell Biology, 103, July 1986, 49-62.

Cortical Cataract

Eye – Brain ConnectionThe Lens and Alzheimer’s Disease

Harvard Medical School

Eye – Brain ConnectionAD 79-year-old woman AD 68-year-old woman

Dashed arc indicates extent of supranuclear cataract. Source, lancet

Misfolded Protein in Brain (Autopsy)

A Sick Eye = A Sick Brain

Misfolded Protein in Lens (living patient)

32

Measuring Neurodegeneration Lens Evaluation – Cortical Cataract Process

1. Coma Aberration

2. Pseudo Exfoliation

3. Cortical Fibril

4. Cortical Spokes5. Cortical Cataract

Measuring Neurodegeneration Cortical cataract specific wavefront aberration

Measures Optical Path Deviation (OPD)

maps the total refractive power errors of the lens, with

specificity.

The early lens changes represent the initial phase of the misfolded protein process. Aberrations occur years before pseudoX and cortical

cataract. These changes pre-date AD by 20+ years.

The accuracy of the instrument (1,440 data points in 0.4 sec) allow for monitoring the efficacy of treatment.

Measuring Neurodegeneration Cortical cataract specific wavefront aberration

34

Measuring Neurodegeneration Oculus Pentacam System

This instrument objectively quantifies a number of parameters involving the lens.

1024

•Accurate and reproducible measurement of cataract•Study progressive change in the lens•Classification of cataract•184,320 Profiles in 0.5 sec.•Measure rate of misfolded protein accumulation in relation to future development of AD

The Answer to Early Diagnosis & Treatment Monitoring of Alzheimer’s Is in the Eye –

The Next Big Thing –

Tau Protein

Measuring Tauopathies – Optic Nerve AnalyzerDr. Alzheimer’s believed this was the cause of AD (1907).

GDx Optic Nerve Analyzer – Measures Tau Protein Structure. They are uniform and polarize light.

In AD patients, uniformity is disrupted and retarded (due to changes in Tau) and light polarization changes.

Amyloid is dead as a therapeutic target.Tauopathies is emerging as the “new” strategy.

Richter-Landsberg C et. Al. Int J De Neuroscience. 2004 No;22(7):443-51

http://legacy.revoptom.com/handbook/oct02_sec4_9.htm

Summary

1024

• Sick Eye in a Sick Body• Eye Pathologies correlate to cardiovascular and

neurodegenerative disease• Eye is easily assessable• Eye may be more susceptible to disease – thus earlier onset• AMD – Vascular disease• Glaucoma – Neurodegenerative disease• RNFL – Biomarker for neurodegeneration• Lens – Cortical cataract = Alzheimer’s peptide• Lens – Nuclear cataract = Misfolded protein (stem cell

disease?) = Vascular disease• RNFL – microtubules – study tau hyperphosphorylation

The Answer to Early Diagnosis & Treatment Monitoring of Alzheimer’s Is in the Eye –

Outcome-Based Approach

Hope for the Afflicted:

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• Treatment versus Treatability

• “Inflammatory blockade restores adult hippocampal neurogenesis.” – Stanford U.

Interpretation: Stopping (the cause of) inflammation leads to the birth of new neurons and the restoration of brain function and memory.

Hope for the Afflicted:

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The Answer to Early Diagnosis & TreatmentMonitoring of Alzheimer’s Is in the Eye

“The experimenter who does not know what he is looking for will not understand what he finds.” – Claude Bernard

"Vulnerable plaque formation from obstruction of vasa vasorum by homocysteinylated and oxidized lipoprotein aggregates complexed with microbial remnants and LDL autoantibodies." – McCully, Ravnskov

Hope for the Afflicted:

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Clinical Approach:

1.Eye Screening2.Immune Health Status3.Tissue Health4.Homeostasis5.Root Causes6.Treatment/Disease Management